Oncogene (2006) 25, 6758–6780
& 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00
www.nature.com/onc
REVIEW
NF-jB and the immune response
MS Hayden1, AP West1 and S Ghosh1,2
1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA and 2Department of Molecular
Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA
One of the primary physiological roles of nuclear factor-
kappa B (NF-jB) is in the immune system. In particular,
NF-jB family members control the transcription of
cytokines and antimicrobial effectors as well as genes that
regulate cellular differentiation, survival and proliferation,
thereby regulating various aspects of innate and adaptive
immune responses. In addition, NF-jB also contributes to
the development and survival of the cells and tissues that
carry out immune responses in mammals. This review,
therefore, describes the role of the NF-jB pathway in the
development and functioning of the immune system.
Oncogene (2006) 25, 6758–6780. doi:10.1038/sj.onc.1209943
Keywords: NF-kB; T-cell receptor; B-cell receptor;
inflammation; TLR; hematopoiesis
Introduction
The discovery and characterization of the nuclear
factor-kappa B (NF-kB) family of transcription factors
resulted from studies in two major areas of research:
immunology and cancer biology. Although the role of
NF-kB in cancer biology is becoming progressively
better established, historically much of our current
knowledge of NF-kB resulted from efforts directed at
understanding the regulation and function of the
immune response. In keeping with the critical role
played by NF-kB in different areas of immunology,
numerous excellent reviews have been published cover-
ing the role of NF-kB in Toll-like receptor (TLR) and
antigen receptor (AgR) signaling, lymphoid organo-
genesis and hematopoiesis (Mebius, 2003; Bonizzi and
Karin, 2004; Hayden and Ghosh, 2004; Lin and Wang,
2004; Siebenlist et al., 2005; Akira et al., 2006). This
review will, therefore, attempt to provide a more
comprehensive, if less detailed, review of the diverse
functions of NF-kB in immunology, with the goal of
illuminating how it is that so much in immunology
seems to revolve around this family of transcription
factors.
Correspondence: Professor S Ghosh, Yale University School of
Medicine, Department of Immunobiology, 300 Cedar Street, New
Haven, CT 06510, USA.
E-mail: sankar.ghosh@yale.edu
Considered broadly, mammalian immune responses
can be divided into innate and adaptive responses. The
immune response begins with the host recognizing the
presence of foreign pathogens, followed by responses at
the cellular, tissue and organismal levels, that ultimately
lead to the clearance of the pathogen. As such, immune
responses can be broken down into individual signal
transduction events through which changes in the
extracellular environment elicit altered gene expression
at the cellular level. In a remarkable number of
instances, NF-kB is the transcription factor that
mediates these transcriptional changes. The gene pro-
ducts characteristic of early events in immune responses
include cytokines and other soluble factors that propa-
gate and elaborate the initial recognition event. The
activation and modulation of NF-kB is also a common
target of these factors. Thus, in a surprising number of
situations NF-kB mediates the critical changes that are
characteristic of innate and adaptive immune responses.
In mammals, the NF-kB family is composed of five
related transcription factors: p50, p52, RelA (aka p65),
c-Rel and RelB (see Gilmore, 2006). These transcription
factors are related through an N-terminal DNA-
binding/dimerization domain, called the Rel homology
domain, through which they can form homodimers
and heterodimers, which bind to a variety of related
target DNA sequences called kB sites to modulate
gene expression. RelA, c-Rel and RelB also contain
C-terminal transcription activation domains (TADs),
which enable them to activate target gene expression. In
contrast, p50 and p52 do not contain C-terminal
transactivation domains; therefore, p50 and p52
homodimers can repress transcription unless they are
bound to a protein containing a TAD, such as Bcl-3.
Alternatively, p50 and p52 often form heterodimers
with RelA, c-Rel or RelB and act as transcriptional
activating dimers.
In most cells, NF-kB complexes are inactive, residing
primarily in the cytoplasm in a complex with any of the
family of inhibitory IkB proteins. When the pathway is
activated, the IkB protein is degraded and the NF-kB
complex enters the nucleus to modulate target gene
expression. In almost all cases, the common step in this
activating process is mediated by an IkB kinase (IKK)
complex, which phosphorylates IkB and targets it for
proteasomal degradation (see Scheidereit, 2006). The
IKK complex consists of two catalytically active kinases
(IKKa and IKKb) and a regulatory scaffold protein,
NEMO. In what is called the canonical (or classical)

pathway, IKKb and NEMO are required for the
activation of complexes such as p50/RelA, p50/c-Rel,
etc., whereas IKKa is relatively dispensable. Conversely,
in the non-canonical (or alternative) pathway IKKa
alone controls the activation of complexes that are
inhibited by the IkB protein p100. These two NF-kB
pathways can be activated by overlapping but distinct
sets of stimuli, and also target activation/repression of
overlapping but distinct sets of target genes. One of the
most conserved functions of the NF-kB signaling
pathway is the regulation of the immune system; indeed,
NF-kB is even the primary regulator of innate immunity
in insects such as Drosophila and mosquitoes (see
Minakhina and Steward, 2006). This review focuses on
the vast role played by NF-kB in mammalian immunity.
Development and formation of the immune system
The mammalian immune system consists of a function-
ally linked group of anatomically disparate tissues and
cell types. The dispersed cellular components of the
immune system that arise from the bone marrow receive
much of the attention in immunology and the study of
NF-kB has likewise focused on its role in leukocytes.
However, lymphoid organs that facilitate coordination
and dissemination of immune responses carried out by
immune cells are also key sites of NF-kB function.
Therefore, whereas this section is largely concerned with
the role of NF-kB in hematopoiesis, the role of NF-kB
in lymphoid organogenesis is also discussed briefly.
NF-kB and hematopoiesis
Most cells of the immune system are subject to rapid
turnover. This process requires the regulation of the
competing forces of cell proliferation and cell death –
processes heavily influenced by NF-kB-regulated genes.
Bone marrow-derived hematopoietic cells in particular
are subject to high levels of turnover and consequently
are particularly sensitive to changes in rates of apoptosis
or proliferation. Likewise, during immune responses
immune cells selectively undergo rapid expansion that
must be resolved by targeted cell death. Although the
role of NF-kB in development and homeostasis of
hematopoietic cells has focused largely on B-cell and
T-cell maturation, it is likely that as our understanding
increases of the pathways responsible for the develop-
ment of natural killer (NK) cells, dendritic cells (DCs),
macrophages, etc. our appreciation for the role of NF-kB
in the biology of these cell types will also expand.
Hematopoietic components of the immune system
include cells of the lymphoid, myeloid and granulocytic
lineages. These lineages give rise to T cells, B cells,
monocytes, macrophages, DCs (both myeloid and
lymphoid), NK cells, basophils, eosinophils, neutrophils
and mast cells (Figure 1). Many cells of the body can
contribute to immune responses; however, these bone
marrow-derived cells are the core constituents of both
the innate and adaptive immune responses. Although
NF-kB generally plays a prosurvival role in these cells,
NF-jB and immunology
MS Hayden et al
6759
its function during hematopoiesis is far more nuanced
than one might expect. In the current review, we limit
our discussion to those instances where the role for
NF-kB is illustrative of its broader functions in the
immune system.
Before delving into specific aspects of NF-kB function
in hematopoiesis, it is worthwhile to discuss the short-
comings of the experimental approaches that are used.
For example, embryonic lethality of RelA knockout
mice prevents straightforward analysis of the hemato-
poietic events that are relevant to adult animals. In other
instances, severe defects in lymphoid organogenesis in
the absence of NF-kB make it difficult to determine
whether the observed defects are intrinsic to the
hematopoietic lineage or are due to alterations in the
relevant organ, for example, stromal tissues, within
which hematopoietic development occurs. In some
instances, such as for RelA or IKKb knockouts,
embryonic lethality can be rescued by deletion of the
tumor necrosis factor-receptor (TNF-R) or tumor
necrosis factor-alpha (TNFa), which permits analysis
of hematopoiesis in these mice, but potentially distorts
certain aspects of the hematopoietic pathway. Similar
concerns apply to adoptive transfer experiments that
can be influenced by the cytokine milieu to which
transferred cells are exposed. In each case, therefore, one
must ask whether the defect exhibited by a cell lacking
some component of the NF-kB pathway is relevant to
the course of normal hematopoiesis or simply to the
experimental system being employed. Finally, there are
numerous instances where one NF-kB family member
can complement the function of another member, or
alternatively, where the absence of one family member
impedes the function or expression of other family
members. Nevertheless, despite these limitations, genetic
analysis has unequivocally illustrated a key role for
NF-kB in the development and survival of hemato-
poietic cells.
NF-kB in development of innate immune cells
DC development is largely dependent on canonical
NF-kB complexes, although a particular subset appears
to require only the non-canonical RelB containing
NF-kB complexes. RelB is known to facilitate the de-
velopment of DCs (Burkly et al., 1995; Weih et al.,
1995); specifically development of CD8a
, but not
CD8a þ , DCs (Wu et al., 1998). Conversely, double
knockout studies have shown that canonical p50/RelA
complexes are required for the development of both
CD8a þ and CD8a
DCs, but not other myeloid and
lymphoid lineages, most likely by mediating the
response of DCs to TNFa (Ouaaz et al., 2002; Abe
et al., 2003). Survival of DCs in the periphery following
activation tends to be short, but can be prolonged upon
CD40L expression on T cells. CD40L activates both the
canonical and non-canonical NF-kB pathways and
hence DCs deficient in both p50 and c-Rel, or DCs
overexpressing a mutant super-repressor form of IkBa,
demonstrate significantly decreased survival (Ouaaz
et al., 2002; Kriehuber et al., 2005).
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 NF-jB and immunology
MS Hayden et al
6760

Pluripotent HSC

Myeloid Stem Cell Lymphoid Stem Cell

Platelets

Basophil Granulocyte-Monocyte
Erythrocytes Progenitor Progenitor T cell B cell NK cell

Basophil Mast Cell Eosinophil

Monocyte Neutrophil Dendritic Cells

Macrophage

Figure 1 Schematic of NF-kB in hematopoiesis. Red arrows indicate stages in which NF-kB activation is thought to contribute
negatively and green arrows indicate a positive function in the development of the indicated lineages. Curved arrows indicate examples
in which NF-kB contributes to the survival of the mature cell population, either in the resting state or during immune responses. Gray
arrows indicate developmental events for which NF-kB plays no role or for which the role of NF-kB has not being clearly
demonstrated. See the text for details.

IkBa knockout mice display robust granulocytosis
(Beg et al., 1995), and suggest an antiapoptotic role
for NF-kB during granulocyte development. Likewise,
NF-kB has an antiapoptotic role in mature granulocytes.
For example, neutrophils, which undergo daily turnover
and rapidly apoptose in vitro, exhibit accelerated
apoptosis as well as sensitization to proapoptotic stimuli
following NF-kB inhibition. Unlike lymphocytes, which
are relatively long-lived in the absence of activation,
protection from apoptosis in neutrophils is more
important during the inflammatory response than in
homeostasis. Indeed, many TLR ligands increase
neutrophil survival in vitro, likely due to NF-kB-
mediated expression of antiapoptotic genes (Francois
et al., 2005). Although neutrophils are capable of
activating NF-kB in response to many pro-inflamma-
tory stimuli (McDonald, 2004), they lack p52 and RelB
(McDonald et al., 1997), the very subunits that are
crucial for the maintenance of long-lived lymphocytes.
Thus in the case of neutrophils, NF-kB fulfills its
predicted role as a prosurvival and proinflammatory
factor.
The general granulocytosis observed in IkBa knock-
out mice suggested that an antiapoptotic role could be
broadly assigned to NF-kB in this lineage. However,
chimeras generated with cells from ikba
/
ikbe
/
mice
(i.e., lacking IkBa and IkBe) instead display a modest
defect in both myelopoiesis and granulopoiesis of
transferred cells (Goudeau et al., 2003), and a
Oncogene
pronounced defect in NK cells and lymphoid lineages
(Samson et al., 2004). Therefore, elevated levels of
NF-kB activity in these cells appears to exert a proapop-
totic effect. Thus, it appears that the role of NF-kB in
granulopoiesis is selective and cell-type-specific.
Furthermore, as described for lymphocyte development
(below), the requirement for individual NF-kB subunits
is not uniform at different developmental stages.
NF-kB in development of B and T cells
As in cells of the innate immune system, NF-kB is vital
for the development and function of adaptive immune
cells (Siebenlist et al., 2005). Although lymphocytes may
exhibit great longevity in the periphery, their selection in
the bone marrow and thymus is characterized by a high
rate of apoptosis. As a consequence, the antiapoptotic
properties of NF-kB play a key role in lymphopoiesis.
The centrality of its antiapoptotic function is supported
in part by the demonstration that most of the require-
ments for NF-kB during T-cell development can be
overcome by transgenic expression of the prototypical
antiapoptotic factor Bcl-2 (Sentman et al., 1991). The
necessity of NF-kB for lymphopoiesis is strikingly
illustrated in human genetic diseases wherein the gene
encoding NEMO is inactivated by mutation (see
Courtois and Gilmore, 2006). Because the NEMO gene
is located on the X-chromosome, it is usually subject to
random inactivation in individual cells in females.

However, in female patients who are heterozygous for a
mutant version of NEMO all peripheral lymphocytes
possess an intact NEMO gene, rather than the 50%
predicted by random inactivation, suggesting that in the
absence of NEMO-dependent NF-kB signaling, B and T
cells fail to develop.
The effects of NEMO inactivation in both mice and
humans solidify the role of NF-kB in lymphopoiesis,
even though the details by which NF-kB functions in
this process remain obscure. NF-kB plays diverse roles
in lymphocyte development that can be grouped
according to when in development it functions – that
is, before, during or after pre-AgR signaling. Although
no single NF-kB subunit knockout mouse has as severe
of a phenotype as NEMO deficiencies with regard to the
generation of mature lymphocytes, double knockouts
demonstrate that the antiapoptotic function of NF-kB is
important in the maturation and survival of lympho-
cytes. For example, loss of both of the canonical NF-kB
family members p50 and RelA, or both RelA and c-Rel,
halts development early in lymphopoiesis, before
expression of the pre-AgRs (Horwitz et al., 1997;
Grossmann et al., 1999), suggesting that NF-kB is
involved in the expression of antiapoptotic factors
required for early lymphoid cell survival in response to
proapoptotic stimuli (Figure 2). In fact, early CD34 þ
bone marrow cells can activate NF-kB in response to
TNFa, and in these cells NF-kB acts as a prosurvival
factor (Pyatt et al., 1999).
Evidence suggests that expression of the pre-AgR
leads to survival signals that depend, at least in part, on
NF-kB. For example, pre-T-cell receptor (pre-TCR)
expression in double negative (DN; CD8
CD4
) thy-
mocytes coincides with high levels of NF-kB activity,
and NF-kB activity at this stage is necessary for DN
survival and maturation (Figure 2). Therefore, enforced
IKKb activation eliminates the requirement for TCR
recombination, whereas inhibition of NF-kB by expres-
sion of an IkBa super-repressor decreases DN thymo-
cyte maturation and survival (Voll et al., 2000).
Signaling through the pre-B-cell receptor (pre-BCR)
also likely induces antiapoptotic signals through NF-kB.
Consequently, the reduced pre-B-cell population seen
upon expression of the IkBa super-repressor in bone
marrow cells can be rescued by overexpression of the
antiapoptotic NF-kB target gene Bcl-XL (Feng et al.,
2004; Jimi et al., 2005). However, whereas evidence
points toward NF-kB-mediated production of antia-
poptotic factors it remains unclear how NF-kB is
activated downstream of the pre-AgR.
Selection of DP (double positive; CD4 þ CD8 þ )
thymocytes depends on the ability of their TCR to
recognize peptide:MHC (major histocompatibility com-
plex) complexes. Thymocytes that express a TCR that is
unable to bind MHC die in a process termed ‘death by
neglect’, whereas those that bind peptide:MHC are
either positively or negatively selected depending on the
strength of this interaction. Thymocytes that bind self-
peptide:MHC with very high affinity are likely to be
self-reactive, and hence are deleted through negative
selection. Thus, only DP thymocytes that recognize
NF-jB and immunology
MS Hayden et al
6761
Periphery
Common Bone Marrow Thymus
Lymphoid
Precursor
Pro-B cell DN
Thymocyte
Pre-B cell
Immature DP
B cell Thymocyte
Transitional SP
B cell Thymocyte
Spleen
Naive B cell Naive T cell
Figure 2 NF-kB function during lymphopoiesis. NF-kB plays a
prosurvival role in common lymphoid precursor cells that give rise
to B- and T-cell lineages. B-cell development occurs in the bone
marrow, where NF-kB protects pre-B cells from proapoptotic
stimuli including TNFa. Signaling to NF-kB through the pre-B-cell
receptor mediates survival of pre-B-cells that then undergo light
chain recombination to produce a functional B-cell receptor.
Expression of BCR leads to NF-kB-dependent differentiation into
immature B cells. High levels of BCR signaling, that is, through
recognition of self-antigen, results in negative selection through the
loss of NF-kB activity. Transitional B cells exit the bone marrow
and migrate to the spleen where they mature and differentiate, a
process that also requires NF-kB. T-cell development occurs
following migration of precursor cells into the thymus. Stimulation
of NF-kB through pre-TCRa provides a prosurvival signal
allowing recombination of the TCRa chain and maturation to
the DP stage. Optimal signaling through the TCRa/b complex
induces NF-kB-dependent survival pathways, whereas a failure
to signal or high-level signaling results in death by neglect or
negative selection, respectively. NF-kB activity is required for the
maintenance of long-lived B and T cells.
self-peptide:MHC with an affinity that falls within a
defined range are positively selected to become single-
positive T cells. Somewhat counterintuitively, it appears
that NF-kB functions in both positive and negative
selection of thymocytes. During negative selection,
NF-kB facilitates the induction of apoptosis following
high-affinity TCR ligation (Hettmann et al., 1999; Mora
et al., 2001b), perhaps by facilitating expression of
proapoptotic genes and the consequent sensitization to
proapoptotic signals (French et al., 1996; Kishimoto
et al., 1998). The role of NF-kB in positive selection of
thymocytes is more in keeping with the better-estab-
lished role of NF-kB as an inducer of antiapoptotic
genes. Unlike in thymocytes, however, NF-kB functions
as a prosurvival factor during negative selection of
B cells. Immature B cells display constitutive NF-kB
activity that is down-regulated following BCR ligation
Oncogene
 NF-jB and immunology
MS Hayden et al
6762
(Wu et al., 1996). Decreased NF-kB activity might then
sensitize these cells to proapoptotic signals. Interest-
ingly, some signaling components required for NF-kB
activation in mature B and T cells can be genetically
disrupted without affecting their development, suggest-
ing that pathways leading to activation of NF-kB in
developing B or T cells differ significantly from the
pathways engaged following AgR ligation in mature
lymphocytes.
Following positive and negative selection, DP thy-
mocytes must make a lineage commitment and become
single positive (SP) thymocytes (CD4 þ CD8
or
CD4
CD8 þ ), which shortly thereafter emigrate from
the thymus. Analyses of kB-site luciferase transgenic
reporter mice have shown that CD8 SP cells have
significantly higher levels of NF-kB activity than CD4
SP thymocytes (Voll et al., 2000). Conversely, the
antiapoptotic factor Bcl-2 is more highly expressed in
CD4 than CD8 cells, suggesting that CD8 SP thymo-
cytes are more dependent on NF-kB for survival.
However, during the course of the development from
the DP stage to emigration from the thymus, both DP
and SP lineages require NF-kB. Targeted deletion of
floxed-NEMO using cd4-promoter-driven Cre recombi-
nase expression, or overexpression of kinase dead
IKKb, results in loss of mature peripheral T cells
(Schmidt-Supprian et al., 2004). These data strongly
suggest that NF-kB activation is required for late stages
of T-cell development; however, ikkb
/
,tnfr1
/
double
knockouts, ikkb
/
chimeras or cd4-Cre IKKb condi-
tional knockouts are not defective in the production of
naı̈ve T cells (Senftleben et al., 2001b; Schmidt-Supprian
et al., 2004), suggesting a requirement for NEMO but
not IKKb.
Immature B cells exit the bone marrow, becoming
transitional B cells, and complete development into
either follicular or marginal zone B cells. NF-kB-
regulated expression of prosurvival factors is important
to these final steps of B-cell development (Grossmann
et al., 2000). Interestingly, the activation of NF-kB in
late B-cell maturation is the result of signaling by both
canonical and non-canonical NF-kB pathways. Thus
deficiency in NEMO, IKKa or IKKb decreases the
numbers of mature B cells (Kaisho et al., 2001;
Senftleben et al., 2001b; Pasparakis et al., 2002).
Likewise, either p50/p52 or RelA/c-Rel double knock-
out progenitor cells are defective in their ability to
mature beyond the transitional B-cell stage (Franzoso
et al., 1997; Grossmann et al., 1999). A requirement for
both the canonical and non-canonical NF-kB pathways
may explain why deletion of p50 and p52 produces a
more complete block in B-cell development than loss of
RelA and c-Rel. Although both canonical and non-
canonical NF-kB pathways are functional during B-cell
development, recent work (Batten et al., 2000;
Schiemann et al., 2001; Claudio et al., 2002) has under-
scored the importance of BAFF ligation in selectively
activating the non-canonical NF-kB pathway and the
consequent expression of antiapoptotic Bcl-2 family
members in transitional B cells (see Mackay et al., 2003).
Indeed, BAFF knockout mice exhibit a complete failure
Oncogene
of transitional B-cell maturation, which mirrors that
seen in Bcl-XL knockout mice (Motoyama et al., 1995;
Gross et al., 2001; Schiemann et al., 2001). Thus, only
those knockouts that target both the canonical and non-
canonical NF-kB pathways have an effect that approx-
imates the phenotype seen in BAFF or Bcl-XL
deficiency.
NF-jB and lymphoid organogenesis
In addition to its role in the development of cells that
directly mediate immune responses, NF-kB also plays
an important role in the development and function of
primary and secondary lymphoid tissues. Primary
(central) lymphoid organs include the bone marrow
and thymus whereas secondary (peripheral) lymphoid
organs include lymph nodes (LNs), Peyer’s patches,
mucosal-associated lymphoid tissue (MALT) and the
spleen. Among the primary lymphoid organs, the bone
marrow remains active throughout life, whereas thymic
activity dwindles with the onset of adulthood. The
secondary lymphoid tissues are associated with the
maintenance and activation of mature lymphocytes, and
provide an environment within which the interaction of
lymphocytes and other leukocytes can be carefully
orchestrated. Although there is clearly a role for NF-kB
in the development and regulation of bone, this role has
not yet been clearly correlated with effects on hemato-
poiesis (Jimi and Ghosh, 2005). Careful anatomical and
histological examination of NF-kB-deficient mice has
resulted in NF-kB being assigned an increasingly
prominent role in lymphoid organogenesis.
Secondary lymphoid organs
The secondary lymphoid organs have highly charac-
teristic structural features that are crucial to the
development and activation of lymphocytes. Analysis
of the role of NF-kB in lymphoid organogenesis in
knockouts has been complicated by the necessity of
interfering with the TNF response to rescue the lethality
associated with NF-kB deficiency. The initial events of
lymphoid organogenesis involve the association of
lymphotoxin (LT)a1b2-expressing hematopoietic cells
and vascular cell adhesion molecule-1 (VCAM1)-
expressing stromal cells (for a review see Mebius,
2003). This interaction initiates a positive feedback-
signaling loop in which NF-kB plays a prominent role
(Figure 3). Cytokines implicated in this signaling loop –
LTa1b2, RANKL (receptor activator of NF-kB ligand)
and TNFa – are known to activate NF-kB. Also,
mediators of lymphoid organogenesis and homeostasis,
such as the adhesion molecules ICAM (intercellular
adhesion molecule), VCAM, PNAd (peripheral node
addressin), GlyCAM-1 (glycosylation-dependent cell
adhesion molecule) and MadCAM (mucosal addressin
cellular adhesion molecule), cytokines including TNFa,
and organogenic chemokines such as CXCL12 (GRO/
MIP-2), CXCL13 (BLC), CCL19 (ELC) and CCL21
(SLC), are regulated by NF-kB.

Chemokines
VCAM-1
Hematopoietic
cell
α4β1
LTα1β2
LTβR
RANK Local stromal
RANKL
cell
Figure 3 NF-kB function in the early events of lymphoid
organogenesis. NF-kB is a vital part of the positive feedback loop
between hematopoietic and stromal cells that comprises the early
events of lymphoid organogenesis. LTa1b2-expressing hematopoie-
tic cells induce production of VCAM-1 through the canonical
NF-kB pathway and chemokines through the non-canonical
(IKKa-dependent) pathway in LTbR-expressing stromal cells.
Stromal expression of chemokines induces the upregulation of
integrins (a4b1) on hematopoietic cells resulting in increased
recruitment of LTa1b2-expressing cells and signaling through
stromal LTbR. RANKL stimulation of NF-kB through TRAF6
is also crucial for the upregulation of LTa1b2 in hematopoietic cells.
Lymphoid organogenesis exhibits distinct requirements
for both the canonical and non-canonical NF-kB
pathways. Signaling through TNF-R, LTbR and
RANK activates canonical RelA-containing complexes
and, hence, it is not surprising that rela
/
/tnfr1
/

double knockout mice lack Peyer’s patches and LNs
and exhibit disorganized spleens (Alcamo et al., 2002).
The requirement for RelA in development of these
tissues lies with the stromal cells and is likely due to a
combination of effects: regulation of apoptosis (e.g., that
induced by TNF); regulation of expression of orga-
nogenic factors including VCAM and LTa1b2; and en-
hancement of the non-canonical p52/RelB pathway
through the LTbR signaling pathway.
Several lines of evidence highlight the importance of
the non-canonical pathway and activation of p52/RelB
complexes in LN development. Mice with a point
mutation in nik (aly/aly mice) lack multiple secondary
lymphoid organs (Miyawaki et al., 1994; Koike et al.,
1996; Shinkura et al., 1999) and share several pheno-
typic similarities with lymphotoxin and IKKa single
knockout animals (Mebius, 2003; Bonizzi and Karin,
2004). p52/RelB, which is activated downstream of NIK
and IKKa, is thought to be the primary transcriptional
mediator of several key organogenic factors including
CXCL12, CXCL13, CCL19, CCL21 and MadCAM-1
(Yilmaz et al., 2003). The p52 single knockout lacks
NF-jB and immunology
MS Hayden et al
6763
normal B-cell follicles, germinal centers (GCs) and
Peyer’s patch development (Caamano et al., 1998;
Franzoso et al., 1998; Paxian et al., 2002); RelB is
likewise also required for Peyer’s patch development
(Yilmaz et al., 2003). Although LN development occurs
in RelB knockout mice, the nodes are small at birth and
are resorbed perinatally. In addition to LTbR, knock-
outs of RANK, which likewise signals through the non-
canonical pathway, also lack peripheral LNs (Dougall
et al., 1999).
Splenic architecture is crucial for B-cell development
as well as for the initiation and maturation of B-cell
responses. The spleen is divided histologically into white
and red pulp zones. Macrophages in the red pulp are
responsible for destroying erythrocytes that are da-
maged or have reached the end of their lifespan. The
white pulp is populated by splenic lymphocytes and
consists of B-cell follicles and T-cell zones. Splenic
architecture allows for dynamic changes, most notably
in the formation of GCs, during the initiation and
maturation of B-cell responses. Multiple NF-kB knock-
outs exhibit defects in some aspect of splenic architec-
ture; however, as for other lymphoid organs, the
analysis of splenic architecture has been complicated
by defects that occur upon deletion of TNF-R used to
rescue the embryonic lethality. Nevertheless, there has
been considerable progress in deciphering the role of
NF-kB family members in development and mainte-
nance of splenic architecture. Mice in which RelA has
been targeted for deletion exhibit aberrant segregation
of B- and T-cell areas and defects in one particular
macrophage population, the metallophilic marginal
zone macrophages. In addition, rela
/
/tnfr1
/
spleens
have a more pronounced defect in GC generation
following immunization, than do tnrf1
/
mice (Alcamo
et al., 2002). However, it is worth emphasizing that
defects observed in tnfr1
/
animals may, in fact, be due
to changes in RelA-dependent responses, and it is
possible that the role of the RelA/canonical NF-kB
pathway in the spleen is underappreciated.
The importance of the non-canonical pathway in the
spleen has been observed in multiple circumstances.
Mice in which non-canonical pathway components,
RelB, NIK or IKKa, have been inactivated demonstrate
severe defects in splenic architecture, similar to that seen
in ltbr
/
spleens. These defects largely reflect deficien-
cies in splenic stromal cells (Miyawaki et al., 1994;
Koike et al., 1996). Mice deficient in the non-canonical
pathway fail to segregate B-cell–T-cell zones and FDC
networks, and they fail to form GCs following
immunization. Marginal zone macrophages, which line
the border between red and white pulp areas, are also
absent or disorganized in RelB, p52, NIK or IKKa
knockouts (Franzoso et al., 1998; Weih et al., 2001).
Some splenic defects are also attributable to effects on
hematopoietic cells. For example, the presence of
metallophilic marginal zone macrophages depends on
p52 (Franzoso et al., 1997). Finally, knockout of the
atypical IkB family member BCL-3 also leads to
alterations in lymphoid architecture that are reminiscent
of those seen in the absence of p52, with which BCL-3
Oncogene
 NF-jB and immunology
MS Hayden et al
6764
forms a transcriptionally active complex. BCL-3 knock-
out mice lack splenic GCs, and although they exhibit
normal serum antibody levels, they fail to develop
antigen-specific humoral responses (Sha et al., 1995;
Caamano et al., 1996; Franzoso et al., 1997; Schwarz
et al., 1997).
In summary, both the canonical and non-canonical
NF-kB pathways are required for the development of
most secondary lymphoid organs. However, the role of
the non-canonical pathway, as assessed by examining
mice deficient for IKKa, p52, NIK or RelB, is especially
important both during organogenesis and maintenance
of splenic architecture. Recent data suggest that the
non-canonical pathway is also important in thymic
development and organization (Burkly et al., 1995; Weih
et al., 1995; Kajiura et al., 2004; Kinoshita et al., 2006).
However, it is important to note that canonical NF-kB
pathway function in these events may be underappre-
ciated owing to embryonic lethality and complicated by
the defects introduced by crossing them onto the tnfr
/

background. Nevertheless, our understanding of non-
canonical pathway function in secondary lymphoid
organs is consistent with the ability of RelB-containing
complexes to regulate genes encoding key organogenic
chemokines and adhesion molecules that direct leuko-
cyte trafficking. The functional consequences of defects
in these processes are severe and have direct ramifica-
tions for the host’s ability to mount a robust immune
response. Alterations in lymphoid architecture likewise
impede the initiation of the adaptive response as well as
the fine-tuning of this response through processes such
as B-cell affinity maturation.
Role of NF-jB in the innate response
Pattern recognition receptors
To activate an appropriate immune response, the host
must first recognize the presence of pathogens. This
discrimination between self and non-self is an absolute
requirement for the initiation of effector functions, such
as the secretion of cytokines and antimicrobial peptides,
carried out by the cells of the innate immune system. A
number of pattern recognition receptors (PRRs) have
evolved to recognize microbial invaders. These PPRs
include TLRs, members of the CATERPILLAR/NOD
family of cytoplasmic receptors, scavenger receptors and
the complement system. Although epithelial cells are
frequently the first to encounter pathogens, they are also
constantly exposed to non-pathogenic microbes. There-
fore, whereas a variety of TLRs are differentially
expressed in epidermis, gut, pulmonary, urinary and
reproductive epithelium, in many cases it is thought that
both TLR expression and responsiveness is tightly
controlled in these cells. For example, keratinocytes
upregulate TLRs expression and responsiveness follow-
ing transforming growth factor-alpha (TGFa) exposure
(Miller et al., 2005); renal epithelial cells increase
expression of TLR2 and TLR4 in response to IFNg or
TNFa (Wolfs et al., 2002) and intestinal epithelial cells
Oncogene
have been shown to alter TLR expression under
inflammatory conditions (Mueller et al., 2006). How-
ever, sentinel cells of the innate immune system,
particularly tissue resident DCs and macrophages,
express a more complete complement of PRRs, and
thus are likely to bear the largest portion of the burden
in the earliest events of pathogen recognition.
Toll-like receptors
TLRs are evolutionarily conserved PRRs that recognize
unique, essential molecules characteristic of various
classes of microbes (Akira et al., 2006). The function
of TLRs as arbitrators of self/non-self discrimination
highlights their central role in innate immunity as well as
in the initiation of the adaptive immune response. The
11 characterized mammalian TLRs have varied tissue
distribution and serve as recognition receptors for
pathogen-associated molecular patterns (PAMPs) pre-
sent on bacteria, viruses, fungi and parasites. Perhaps
due to the multimeric nature of the TLR extracellular
domain (ED), which consists of multiple leucine-rich
repeats (LRRs), several receptors are capable of
recognizing more than one microbial molecule (Figure 4
and below). Heterodimerization of some TLRs and the
use of co-receptors (e.g., CD14 and MD-2) further
expand the repertoire of PAMPs recognized. As we shall
see below, the ability of TLRs to distinguish between
pathogen types is translated into appropriate innate and
adaptive responses through the selective activation of
NF-kB and other inducible transcription factors. Sig-
nificant progress has been made over the past few years
in deciphering the relevant signaling pathways that
operate downstream of TLRs in particular.
TLR signaling to NF-kB
Ligand binding to TLRs is just now beginning to be
understood at the molecular level. Extracellular LRRs
bind to ligand and, either through receptor oligomeriza-
tion and/or induction of a conformational change across
the plasma membrane, induce the recruitment/activa-
tion of adapter proteins through the Toll/IL-1 Receptor
(TIR) domain. These adapters lead to the activation of
canonical IKKb-dependent complexes, degradation of
IkBa and IkBb, and liberation of, primarily, RelA and
c-Rel containing NF-kB complexes. TLR signaling to
NF-kB is divided into two pathways: those that are
MyD88 (myeloid differentiation primary response gene
88)-dependent and those that are MyD88-independent
(Figure 5). We will base our discussion primarily on
signaling events emanating from TLR4, which despite
having the most complex downstream pathways is the
most thoroughly studied TLR. Clear differences exist in
signaling from other TLRs as noted throughout our
discussion, and it is likely that further specializations
will become apparent as individual TLR signaling
pathways are investigated more thoroughly.
MyD88-dependent signaling to NF-kB. TLR4 signaling
is relatively unique amongst TLRs in that the effector
adaptors are one step removed from the receptor. For

Lipoteichoic Acid (LTA)
Diacyl Lipopeptides
Triacyl Lipopeptides
Yeast Zymosan
Peptidoglycan (PGN)
TLR-2 TLR-6
TLR-1 TLR-2
Gamma-D-glutamyl-meso-
diaminopimelic acid (iE-DAP) NOD1
Muramyl Dipeptide (MDP) NOD2
dsRNA RIG-I
dsRNA
MDA5
Figure 4 PRRs that signal to NF-kB and their cognate ligands. TLRs 3, 7, 8, 9 and 11 have been reported to exhibit endosomal or
intracellular localization whereas NOD1, NOD2, RIG-I and MDA5 function in the cytoplasm.
example, MyD88 recruitment to the receptor complex
depends upon the TIR-domain containing adapter
protein (TIRAP, also known as Mal) (Fitzgerald et al.,
2001; Horng et al., 2002; Yamamoto et al., 2002). TLR2
also requires TIRAP to bridge MyD88 to the receptor;
however it is believed that other MyD88-utilizing TLRs
directly recruit MyD88. Recent reports suggest that the
requirement for these intermediatory adapters is related
to localization of the TLRs to certain domains in the
plasma membrane (Kagan and Medzhitov, 2006; Rowe
et al., 2006). The N-terminal domain of MyD88
contains a death domain (DD) that recruits the DD-
containing serine/threonine kinase interleukin-1-
associated kinase-4 (IRAK-4). IRAK-4 and IRAK-1
form an active complex capable of recruiting the TNF
receptor-associated factor TRAF6 (Figure 5a). The link
between TRAF6 and the IKK complex remains some-
what enigmatic, although a few key players are known.
The kinase TAK1 (TGFb-activated kinase-1) is required
for NF-kB, as well as AP-1 and extracellular signal-
related kinase (ERK), activation downstream of MyD88
(Sato et al., 2005; Shim et al., 2005). Although it is
widely accepted that ubiquitination is a key switch at
this crucial step of NF-kB activation, considerable work
at the molecular level remains to be done to understand
how ubiquitination leads to activation.
In addition to TAK1, another protein, termed ECSIT
(evolutionarily conserved signaling intermediate in Toll
NF-jB and immunology
MS Hayden et al
6765
Lipopolysaccharide (LPS)
Glycoinositolphospholipids
Glucuronoxylomannan Flagellin
Mannan
TLR-4 TLR-5 TLR-10 TLR-12
PFTG TLR-11
UPEC
dsRNA
ssRNA
CpG-DNA
Hemozoin
TLR-3
TLR-9
TLR-7 TLR-8
pathways), was identified because of its interaction with
TRAF6. ECSIT binds to TRAF6 and is required for
TLR and interleulin-1 (IL-1) signaling, but not TNF-
signaling (Kopp et al., 1999; Xiao et al., 2003). Although
these studies suggested that ECSIT functions by
recruiting and activating the kinase MEKK1 (mitogen
activated protein kinase or ERK kinase (MEK) kinase
1) (Kopp et al., 1999; Xiao et al., 2003), the role of
MEKK1 in TLR signaling remains unclear (Xia et al.,
2000; Yujiri et al., 2000). MEKK3-deficient cells,
however, do not transcribe IL-6 following TLR4 or
IL-1R stimulation and exhibit delayed and weakened
NF-kB DNA binding following lipopolysaccharide
(LPS) stimulation (Huang et al., 2004). ECSIT interacts
with both TAK1 and MEKK3 (AP West and S Ghosh,
unpublished observations) and it is, therefore, possible
that ECSIT exerts its role in TLR signaling by
modulating the function of TAK1 and/or MEKK3.
TRIF-dependent signaling to NF-kB
Somewhat unexpectedly, when exposed to LPS,
MyD88
/
cells display partial NF-kB activation, albeit
with slower kinetics than in wild-type cells (Kawai et al.,
1999). When cells are stimulated through TLR3 and
TLR4, TRIF (TICAM-1), a TIR-domain containing
adapter, mediates activation of NF-kB in the absence of
MyD88 (Oshiumi et al., 2003). Furthermore, in the case
Oncogene
 NF-jB and immunology
MS Hayden et al
6766

LPS

TLR4

TIRAP b
a TRAM
c dsRNA
MyD88 TRIF

RIGI
IRAK1

IRAK4

IPS-1
IKKi
FADD d
TRAF6 Ub TBK1 NOD2
RIP1

Ub MDP
ECSIT TRAF6 RIP1
TAK1 P

Ub IRF3
NEMO RIP2
P
Ub
NEMO
P
PP
NF- κB

Gene
Transcription

Figure 5 PRR signaling to NF-kB. Signaling through LPS/TLR4 via the MyD88-dependent (b) and TRIF-dependent (a) pathways
converge on IKK activation through TRAFs. Signaling through dsRNA/RIG-I (c) proceeds through ISP1 to IKKi/TBK1 and through
RIP1 to IKK. Signaling from NOD to NF-kB (d) is thought to involve oligomerization of RIP2 and activation of IKK through
induced proximity. See the text for details.

of TLR3, all downstream signaling appears to be TRIF-
dependent. In TLR4 signaling, TRIF is required for
late-phase NF-kB and IRF3 responses, but is not
required for activation of JNK (Yamamoto et al.,
2003). TRIF signaling to NF-kB and IRF3 also appear
to be separately regulated (Figure 5b). Signaling to IRF-
3 occurs through two divergent members of the IKK
family, IKKi (IKKe) and TBK1 (T2K) (Fitzgerald et al.,
2003; Sharma et al., 2003); however, neither kinase is
required for NF-kB activation by LPS or TNFa
(Hemmi et al., 2004; McWhirter et al., 2004). Further-
more, reconstitution of trif
/
cells with mutant TRIF
lacking the TRAF-binding domain selectively restores
induction of IRF3 but not NF-kB. Increasingly, there-
fore, it appears that the events leading from TRIF to
IKK activation share a common set of intermediates as
seen in other NF-kB activation pathways.
TRIF interacts with receptor interacting protein
(RIP)1 and RIP3 through their RIP homotypic interac-
tion motif (RHIM), and rip1
/
embryonic fibroblasts
have decreased NF-kB activation following TLR3-
poly(I:C) signaling (Meylan et al., 2004). Finally,
another TIR-domain containing adapter TRAM
Oncogene
(TRIF-related adapter molecule) functions upstream of
TRIF in MyD88-independent signaling from TLR4.
TRAM is required for IRF3 activation and for the
delayed phase of NF-kB activation following TLR4
engagement. TLR4-induced IRAK activation by
MyD88, however, is unaffected by the absence of
TRAM and TRAM does not function in TLR3 TRIF-
dependent signaling pathways (Fitzgerald et al., 2003;
Yamamoto et al., 2003). Therefore, it appears that
TRAM is only needed for TRIF signaling downstream
of TLR4. Adding further complexity, it has recently
been suggested that TLR4, but not TLR3, TRIF-
dependent NF-kB activation is largely due to IRF3-
induced TNFa rather than to direct signaling to IKK
(Covert et al., 2005; Werner et al., 2005). Although
the applicability of these finding to other cell types is, as
of yet, unclear, these results may be explained by
differences in the recruitment of TRIF to the
receptor; that is, by TRAM in the case of TLR4 versus
directly to TLR3, resulting in changes in the avail-
ability of TRAF binding site or the availability of
additional signaling intermediates at distinct subcellular
localizations.

Negative regulation of TLR signaling
Inflammatory responses are built upon waves of
cytokine production and positive feedback mechanisms.
As a result, tight control must be placed on the initiation
and maintenance of these responses. Multiple negative
feedback loops have been described that involve
proteins that are induced or activated upon TLR
signaling. In a number of instances, the target of these
regulatory mechanisms is the IRAK family of proteins.
For example, IRAK-M (IRAK3) inhibits signaling to
TRAF6 by fixing IRAK-1/4 to the TLR/MyD88
signaling complex; irakm
/
knockouts exhibit enhanced
signaling to NF-kB (Kobayashi et al., 2002). Tollip, an
adapter protein constitutively associated with IRAK, is
phosphorylated and dissociates following IRAK4 acti-
vation (Burns et al., 2000; Zhang and Ghosh, 2002).
Negative regulation of TLR signaling by Tollip in the
intestinal epithelium may prevent inflammatory re-
sponses to commensal bacteria (Melmed et al., 2003).
However, Tollip-deficient cells demonstrate only minor
defects in the production of NF-kB-regulated cytokines
(Didierlaurent et al., 2006). Therefore, it is unclear
whether Tollip indeed functions as initially thought.
SIGIRR (TIR8), a member of the IL-1R family, binds
to Toll/IL-1 receptors, IRAK and TRAF6 and may also
function by inhibiting the association of IRAK with
TLRs (Thomassen et al., 1999; Wald et al., 2003).
SIGIRR deficiency yields prolonged activation of
NF-kB by Toll/IL-1 stimulation consistent with a
regulatory function. Interestingly, SIGIRR is also highly
expressed in epithelial cells, suggesting that it too may
suppress signaling at sites of constitutive microbial
exposure. Finally, suppressor of cytokine signaling-1
(SOCS-1) has been reported to negatively regulate LPS
signaling to NF-kB and socs1
/
mice exhibit an
inflammatory phenotype that is consistent with this
prediction (Kinjyo et al., 2002; Nakagawa et al., 2002).
SOCS-1 may function by directly targeting TIRAP/Mal,
and selectively inhibit TLR4 signaling through the
TIRAP/Mal/MyD88 pathway (Mansell et al., 2006).
In addition to these TLR-specific regulators of
signaling to NF-kB, other proteins function to control
the extent and duration of NF-kB activation. These
factors both set thresholds for activation and help to
prevent uncontrolled, and potentially deleterious, innate
immune responses. The broad array of PAMPs recog-
nized by the TLR system affords the host the ability to
mount responses against many pathogens. Nevertheless,
for some pathogens, TLRs alone are not sufficient, and
some physical spaces, most notably the cytosol, are not
effectively monitored by TLRs.
Cytoplasmic PRRs that activate NF-kB
PRRs that recognize bacterial PAMPs are expressed at
the plasma membrane or with LRRs projecting into the
lumen of vesicles that are topologically related to the
extracellular space. However, in such a system, intra-
cellular pathogens are uniquely protected from detec-
tion. Furthermore, viral infection and the resulting
induction of interferon occurs in many cells that do not
NF-jB and immunology
MS Hayden et al
6767
express the full panoply of antiviral TLRs – suggesting
that other PRRs must be at work. In fact, cells do have
at their disposal families of cytoplasmic PRRs that are
capable of activating NF-kB and other transcriptional
mediators of the innate immune response. Interestingly,
many of these PRRs contain caspase activation and
recruitment domains (CARDs) that are required for
activation of NF-kB following ligand binding. Here, we
provide a brief description of two classes of cytoplasmic
PRRs – CARD-containing members of the CATEPIL-
LAR and DExD/H-box helicase families.
CATEPILLER-NODs. Nucleotide oligomerization
domain proteins (NOD) 1 and 2 are part of a large
family termed the CATEPILLER family, which is
named for CARD, transcription enhancer, R (purine)-
binding, pyrin, lots of leucine repeats (Figure 4). The
NOD-LRR subfamily is typified by the presence of
LRRs and nucleotide oligomerization domains. NOD1,
NOD2 and IPAF have CARDs and can signal to NF-
kB (for a review see Inohara and Nunez, 2003). NOD1
recognizes a peptidoglycan containing meso-diaminopi-
melic acid (meso-DAP) and induces NF-kB through a
canonical pathway that includes activation of IKKb.
NOD2 recognizes muramyl dipeptide, a ubiquitous
component of nearly all bacterial cell walls. Relatively,
few signaling intermediates downstream of NOD-LRRs
are known; however, there is growing evidence that the
CARD-containing kinase RIP2 (RICK) is required for
NF-kB activation. Intriguingly, the ATP-binding cas-
sette of both NOD1 and NOD2 is needed for signaling
(Tanabe et al., 2004). RIP2 binds to NEMO and
therefore is thought to directly mediate activation of
the IKK complex by induced proximity (Inohara et al.,
2000). In this model, ligand-dependent oligomerization
of NOD-LRRs, which is dependent on the ATP-binding
cassette, leads to a scaffold containing multiple RIP2
molecules, which allows trans-autophosphorylation of
neighboring IKK complexes (Figure 5d).
Retinoic acid inducible gene I and melanoma
differentiation-associated gene 5
Two members of the DExD/H-box RNA helicase family
stand out because of the presence of N-terminal CARD
domains. Retinoic acid inducible gene I (RIG-I) and
melanoma differentiation-associated gene 5 (MDA5) are
RNA helicase-containing cytoplasmic proteins. The
RNA helicase domains of RIG-I and MDA5 bind
directly to double-stranded RNA (dsRNA) and induce
production of type I interferons (Kang et al., 2002;
Andrejeva et al., 2004; Yoneyama et al., 2004). Upon
binding to dsRNA, representing either the viral genome
or viral replication intermediate, RIG-I and MDA5
induce the activation of IRF3 and NF-kB. Interestingly,
initiation of these signaling cascade is abrogated by
point mutations in the Walker-type ATP-binding site,
suggesting that their ATPase activity is required for
signaling (Yoneyama et al., 2004). The link between
these two proteins and NF-kB remains somewhat
unclear (Figure 5c); however overexpression of the
Oncogene
 NF-jB and immunology
MS Hayden et al
6768
N-terminal CARD domain alone is sufficient to induce
signaling. Recently, a CARD-containing protein, vari-
ably named CARDIF, IPS1, MAVS and VISA, has
been implicated downstream of RIG-I; however, the
link between this protein and IKKb is unclear (Kawai
et al., 2005; Meylan et al., 2005; Seth et al., 2005; Xu
et al., 2005). It appears, however, that there are
similarities to TRIF mediated signaling, in that RIG-I
activation of NF-kB requires FADD and RIP-1
(Balachandran et al., 2004; Yoneyama et al., 2005).
Recently, it was shown that RIG-I and MDA5
differentially recognize various groups of RNA viruses
and are thus critical for a robust antiviral response
(Kato et al., 2006).
Pathogen recognition in innate immunity
Bacterial recognition
Pathogens recognized by PRRs can be categorized as
bacterial, viral or eukaryotic. In each of these categories,
PAMPs have been described that more or less fit with
existing hypotheses of how pathogen recognition by the
innate immune system should occur (Janeway, 1989).
Both in terms of accessibility and uniqueness to
prokaryotes, the bacterial cell well is a logical source
of PAMPs for TLRs and other PRRs.
LPS was originally thought to be the ligand for
TLR2, but subsequent studies revealed that contaminat-
ing bacterial lipoprotein in LPS preparations is the
actual ligand (Wetzler, 2003). TLR2 also mediates
responses to several Gram-positive bacterial cell wall
components as well as Staphylococcus aureus peptido-
glycan (Takeuchi et al., 2000). Additional work has
shown that TLR2 is involved in the recognition of a
wide range of microbial products and generally func-
tions as a heterodimer with either TLR1 or TLR6
(Ozinsky et al., 2000; Wyllie et al., 2000). The TLR2/
TLR1 heterodimer recognizes a variety of lipoproteins,
including those from mycobacteria and meningococci
(Takeuchi et al., 2002; Wetzler, 2003), whereas the
TLR2/TLR6 complex recognizes mycoplasma lipopro-
teins and peptidoglycan (Takeuchi et al., 2001). Recent
reports have demonstrated that triacylated lipoproteins
from bacteria are preferentially recognized by the
TLR1/TLR2 complex, whereas diacylated lipoproteins
are recognized by the TLR2/TLR6 complex (Takeuchi
et al., 2002). However, additional TLR2 ligands do not
require TLR1 or TLR6 for signaling, implying that
TLR2 recognizes some ligands as a homodimer or
heterodimer with other non-TLR molecules. Such TLR2
ligands include the Gram-positive cell wall component
lipoteichoic acid; the mycobacterial cell wall component
lipoarabinomannan; atypical LPS produced by Legionella,
Leptospira interrogans, Porphyromonas gingivitis
and Bordetella; and porins present in the outer
membrane of Neisseria (Massari et al., 2003; Wetzler,
2003).
The TLR4 ligand LPS, a glycolipid component of the
outer membrane of Gram-negative bacteria, is the most
Oncogene
thoroughly studied and the most potent TLR ligand
known. Trace amounts of LPS activate the innate
immune system via TLR4, leading to the production of
numerous proinflammatory mediators, such as TNFa,
IL-1 and IL-6. TLR4-mediated responses to LPS require
CD14 and MD-2. Other bacterial TLR4 ligands include
Lipid A analogs (Lien et al., 2001) and mycobacterial
components (Means et al., 1999).
TLR5 recognizes flagellin, a protein component of
Gram-negative bacterial flagella and virulence factor for
multiple human pathogens (Hayashi et al., 2001). In
light of the fact that it was thought that proteins would
be too mutable to serve as PAMPs, it is notable that
TLR5 recognizes a highly conserved, central core
structure of flagellin that is essential for protofilament
assembly (Smith et al., 2003). Interestingly, the TLR5
recognition site is masked in the filamentous flagellar
structure, thus indicating that TLR5 recognizes only
monomeric flagellin (Smith et al., 2003). Furthermore,
flagellin appears to bind directly to TLR5 at residues
386–407, as TLR5 mutants lacking this domain are
unable to interact with flagellin in biochemical assays
(Mizel et al., 2003). Recent articles have demonstrated
TLR5-independent recognition of cytosolic Salmonella
typhimurium flagellin via Ipaf, a member of the NOD-
LRR family (Franchi et al., 2006; Miao et al., 2006).
Ipaf-mediated recognition of cytosolic flagellin induces
caspase-1 activation and subsequent IL-1b secretion by
macrophages. TLR11 recognizes a protein PAMP that is
present on uropathogenic Escherichia coli (Zhang et al.,
2004). Although the identity of this ligand is unknown,
its ability to stimulate in a TLR11-dependent manner is
destroyed by proteinase treatment.
Conserved differences in bacterial nucleic acid struc-
tures can also be recognized by the innate immune
system. TLR9 recognizes bacterial DNA containing
unmethylated CpG motifs, and TLR9-deficient mice are
not responsive to CpG DNA challenge (Hemmi et al.,
2000). The low frequency and high rate of methylation
of CpG motifs prevent recognition of mammalian DNA
by TLR9 under physiological circumstances. A recent
report indicated that the intracellular, endosomal
restriction of TLR9 is critical for discriminating between
self and nonself DNA, as host DNA, unlike microbial
DNA, does not usually enter the endosomal compart-
ment (Barton et al., 2006).
Viral recognition
Although viruses are composed entirely of host products
they, nevertheless, have unique components that readily
serve as PAMPs. Nucleic acids are also key viral
PAMPs, and are recognized by TLRs 3, 7, 8 and 9, as
well as by cytoplasmic receptors of the RIG family (as
described above). TLR3 recognizes dsRNA, a common
viral replicative intermediate (Alexopoulou et al., 2001).
TLR3 signaling results in the activation of NF-kB
and IRF3, ultimately leading to the production of anti-
viral molecules, such as type I interferons (IFN-a/b)
(Alexopoulou et al., 2001). The importance of RIG-I-
and MDA5-mediated viral recognition is further

supported by gene-targeting experiments demonstrating
that TLR3 and its adaptor TRIF are not required for
type I IFN production in some virally infected cells,
such as fibroblasts and conventional DCs (Honda et al.,
2003). However, plasmacytoid DCs exclusively utilize
TLR3/TRIF signaling for type I IFN production in
response to RNA viruses and poly(I:C) (Kato et al.,
2005).
Although initially found to recognize synthetic anti-
viral compounds, namely imidazoquinolines, the azo-
quinoline R-848 and loxoribine (Hemmi et al., 2002;
Jurk et al., 2002), TLR7 and human TLR8 are now
known to recognize guanosine- or uridine-rich single-
stranded RNA derived from RNA viruses (Diebold
et al., 2004; Heil et al., 2004; Lund et al., 2004).
Interestingly, mammalian RNA, which contains many
modified nucleosides, is significantly less stimulatory via
TLRs 7 and 8 than bacterial RNA, suggesting that
nucleoside modification allows mammals to distinguish
between endogenous and pathogen-derived RNA
(Kariko et al., 2005). Similar to TLR3, engagement of
these receptors leads to the production of type I IFNs.
TLR9 recognizes viral CpG sequences and induces the
induction of IFN-a (Takeshita et al., 2001; Lund et al.,
2003; Krug et al., 2004). However, as membrane
restriction prevents TLRs from sampling the cytosol
where much of the viral life cycle occurs, cytosolic PRRs
provide comprehensive innate immune recognition. For
example, recognition of cytoplasmic dsDNA leading to
NF-kB activation and type I interferon production has
also been reported, although the relevant receptor has
not yet been identified (Ishii et al., 2006; Stetson and
Medzhitov, 2006). This receptor(s) is predicted to be
important for type I IFN production in response to
viruses and intracellular pathogens, such as Listeria
monocytogenes and Shigella flexneri. Finally, there have
been some reports suggesting that certain viral proteins
function as PAMPs. For example, TLR4 may recognize
respiratory syncytial virus (RSV) F protein (Kurt-Jones
et al., 2000).
Recognition of other pathogens
MyD88-deficient cells demonstrate that many fungal
species are capable of activating TLR pathways,
although the receptors have not always been identified.
TLR4 has been shown to recognize Aspergillus hyphae
(Mambula et al., 2002), and Cryptococcus neoformans
capsular polysaccharide (Shoham et al., 2001). TLR2
and TLR6 are required for recognition of yeast
zymosan, whereas TLR4 is thought to recognize certain
yeast mannans (for a review see Levitz, 2004). The
identification of parasite PAMPs has been more elusive,
and their existence is somewhat controversial. However,
TLR2 heterodimers reportedly recognize various para-
site GPI-anchored proteins and glycoinositolphospholi-
pids from the parasitic protozoa Trypanosoma cruzi
(Campos et al., 2001). Some TLR knockout mice have
been shown to have variable defects in their ability to
defend against various parasites (for a review see
Gazzinelli et al., 2004). Recently, TLR9 has been
NF-jB and immunology
MS Hayden et al
6769
reported to recognize the malarial pigment hemozoin,
a byproduct of heme metabolism in infected erythro-
cytes (Coban et al., 2005) whereas TLR11 recognizes a
profilin-like protein that is conserved in apicomplexan
parasites including Toxoplasma gondii (Yarovinsky
et al., 2005).
Immediate antimicrobial responses
PRRs initiate a complex series of events following
exposure to certain microbial components: the first is the
mounting of immediate antimicrobial responses at the
cellular level. This is an effective and evolutionarily
conserved function of PRRs, and one in which NF-kB
has an important role. The liberation of products with
direct antimicrobial activity occurs early at sites of
pathogen entry. TLR ligation is at least partly respon-
sible for the NF-kB-dependent expression of defensins –
cationic peptides that exert direct bactericidal activity by
inducing membrane permeabilization. Small intestinal
Paneth cells, for example, release large amounts of
a-defensins into the intestinal lumen following exposure
to a variety of bacteria/bacterial products (Ayabe et al.,
2000). The production of antimicrobial nitrogen and
oxygen species, which are acutely toxic to a variety of
microbes, augments the activity of antimicrobial pep-
tides. Production of nitric oxide is mediated in part by
inducible nitric oxide synthase (iNOS), which is partially
regulated by NF-kB. Consequently, iNOS production
results from TLR or NOD-LRR ligation by PAMPs.
Much of the early innate response has been demon-
strated to depend on the canonical NF-kB pathway.
Thus, rela
/
/tnfr1
/
double knockout mice have
increased susceptibility to bacterial infection (Alcamo
et al., 2001). Likewise, B cells from p50
/
mice do not
respond efficiently to LPS, emphasizing the importance
of p50-containing complexes, that is, p50/RelA, p50/
p50/BCL-3 and p50/c-Rel, in TLR signaling (Sha et al.,
1995). As might be expected, TNFR/IKKb double
knockouts show a more pronounced defect in innate
responses owing to the more complete block in
canonical NF-kB pathways, and succumb to infection
more rapidly than rela
/
/tnfr1
/
mice (Li et al.,
1999a, b; Senftleben et al., 2001b). Furthermore, MEFs
from nemo
/
mice do not exhibit NF-kB activation by
LPS or IL-1 (Rudolph et al., 2000). Therefore, activa-
tion of NF-kB responsive genes by the innate immune
system depends on NEMO and likely progresses
through the canonical NF-kB signaling pathway.
Inflammation
There is a staggering amount of literature that correlates
NF-kB activation with inflammation in a wide array of
diseases and animal models. There are, likewise,
numerous studies using gene targeting and inhibitors
of NF-kB that have established that NF-kB plays a
causative role in inflammatory processes. We have
already discussed the role of NF-kB in the survival of
Oncogene
 NF-jB and immunology
MS Hayden et al
6770
leukocytes, and how this role is particularly important
during the responses that include inflammation. Here,
we briefly discuss a few of the additional ways in which
NF-kB regulates inflammation. Inflammation begins
with epithelial or stromal cells of the infected tissue or
tissue resident hematopoietic cells such as mast cells or
DCs recognizing an inflammatory stimulus and propa-
gating proinflammatory signals. These signals lead to
the recruitment and activation of effector cells, initially
neutrophils and later macrophages and other leuko-
cytes, resulting in the tissue changes characteristic of
inflammation – rubor, calor, dolor and tumor (redness,
heat, pain and swelling, respectively).
As for the immediate antimicrobial products dis-
cussed above, NF-kB is responsible for the transcription
of the genes encoding many proinflammatory cytokines
and chemokines. One important early target of these
effectors is the vascular endothelium. Changes in
vascular endothelial cells both recruit circulating leuko-
cytes and provide them with a means of exiting the
vasculature into the infected tissue. NF-kB regulates the
expression of adhesion molecules, both on leukocytes
and endothelial cells, which allow the extravasation of
leukocytes from the circulation to the site of infection
(Eck et al., 1993). Indeed, RelA-deficient mice display a
severe defect in the recruitment of circulating leukocytes
to sites of inflammation (Alcamo et al., 2001).
Recruited neutrophils are the key mediators of local
inflammation and NF-kB is important for the survival
of these cells, which must function in relatively toxic
conditions (Ward et al., 1999). NF-kB is important for
the production of the enzymes that generate prostaglan-
dins and reactive oxygen species (e.g., iNOS and Cox,
both NF-kB target genes) and may, furthermore, be
involved in the signaling induced by prostaglandins
(Poligone and Baldwin, 2001; Catley et al., 2003).
NF-kB has also been implicated in the response to
leukotrienes, which like prostaglandins are short-lived
paracrine effectors, although it is unclear whether this
represents a direct signaling event. Finally, matrix
metalloproteinases (MMPs) also are crucial mediators
of local inflammation and leukocyte chemotaxis; and
their expression is also regulated by NF-kB (Vincenti
et al., 1998; Vincenti and Brinckerhoff, 2002; Lai et al.,
2003).
The pathway from pathogen recognition to proin-
flammatory cytokine production demonstrates a parti-
cular reliance on NF-kB. The immediate targets of
NF-kB-dependent proinflammatory cytokines, such as
TNFa, tend to be receptors that, in turn, activate NF-kB.
Therefore, NF-kB is crucial to the propagation and
elaboration of cytokine responses. TNFa is particularly
important for both local and systemic inflammation,
and it is a potent and well-studied inducer of NF-kB.
TNF-R superfamily signaling
The TNF-R superfamily is remarkably diverse with
more than two-dozen receptors and nearly as many
ligands that are variably expressed throughout the
body. However, despite the physiological diversity of
Oncogene
responses, in most cases signaling converges on the
activation of NF-kB and AP-1. NF-kB activation in
response to TNF signaling induces expression of
antiapoptotic genes such as cIAP1/2 and Bcl-XL (see
Dutta et al., 2006).
TNF family receptors lack intrinsic enzymatic acti-
vity. Instead, signaling is achieved by recruitment of
intracellular adapter molecules that associate with the
cytoplasmic tail of the TNF-R in a signal-dependent
manner (Figure 6a). The recruitment of TNF-R1 to
membrane microdomains, referred to as lipid rafts, with
subsequent assembly of the signaling complex, is
necessary for signaling to NF-kB and prevention of
apoptosis (Hueber, 2003; Legler et al., 2003). Ligation of
TNF-R1 by trimeric TNFa causes aggregation of the
receptor allowing binding of the TNF-R-associated
death domain protein (TRADD). TRADD subse-
quently recruits adapter molecules including TRAF2
a b
RIP1 Ub
FADD
RIP1 Ub
TRAF2/5/6
TRADD
TRAF2/5
TRAF3
TAK1 NIK
MEKK3
Ub
P NEMO
P
P P
NF- κB p100 RelB
Gene
p52 RelB Transcription
Figure 6 TNF receptor superfamily signaling to NF-kB. Activa-
tion of the canonical NF-kB pathway downstream of TNF-RI is
initiated by trimerization through ligand binding and recruitment
of FADD, TRADD, RIP1 and TRAF2/5 to the receptor
(a). TAK1 and MEKK3 are subsequently recruited to the receptor
complex through RIP1, and with TRAF2/5, mediate the activation
of IKK. The phosphorylation and degradation of classical IkBs
require IKKb and NEMO. The non-canonical pathway is mediated
by IKKa through NIK (b). In the resting state, NIK is inactivated/
degraded through an interaction with TRAF3. Upon stimulation,
TRAF3 is inactivated/degraded resulting in the accumulation of
NIK, activation of IKKa, phosphorylation of p100 and liberation
of p100-inhibited NF-kB complexes. Simultaneous activation of
the canonical NF-kB pathway through either TRAF2, 5, or 6
also commonly occurs downstream of receptors that activate the
non-canonical pathway. See the text for additional details.

(Hsu et al., 1996); however, TRAF2 and TRAF5 appear
to play redundant roles in TNF signaling to NF-kB.
TRAF2 or TRAF5-deficient mice have intact TNF
activation of NF-kB, whereas TRAF2/5 double knock-
out cells have substantially reduced TNF-induced IKK
activation (Yeh et al., 1997; Nakano et al., 1999; Tada
et al., 2001). TRAFs may either recruit the IKK
complex directly (Devin et al., 2001) or indirectly
through the serine/threonine kinase, RIP1. RIP1 can
also interact independently with TRADD and is an
essential adapter for TNF-induced NF-kB activation
and protection from apoptosis (Hsu et al., 1996; Ting
et al., 1996; Kelliher et al., 1998; Devin et al., 2000).
Upon ubiquitination, RIP1 can bind directly to NEMO
and recruit IKK independent of TRAF2 (Zhang et al.,
2000). Signaling downstream of RIP1 requires TAK1
for the activation of IKK (Sato et al., 2000; Shim et al.,
2005). Whether TAK1 directly activates IKK or this
process proceeds through an intermediary such as
MEKK3 is not yet clear (Takaesu et al., 2003; Li
et al., 2006). However, it does not appear that TAK1 is
involved in the activation of the non-canonical NF-kB
pathway (Shim et al., 2005).
The non-canonical NF-kB pathway is unique in that
it is independent of IKKb and NEMO and instead
requires IKKa which is phosphorylated by NF-kB
inducing kinase (NIK) (Xiao et al., 2001; Senftleben
et al., 2001a; Claudio et al., 2002; Dejardin et al., 2002;
see Scheidereit, 2006). The key question concerning
signaling by these stimuli is how they are channeled to
NIK and IKKa, even though their receptor signaling
domains resemble those of other TNF family members
(Figure 6b). Because RANKL, BAFF and CD40L may
also activate the canonical pathway through TRAF2/6,
it would appear that the intracellular signaling domain
of these receptors possess additional sequence motifs
that allow their signaling to NIK. This function is
mediated by TRAF3, which interacts with these
receptors. TRAF3 negatively regulates NIK, and under-
goes signal-dependent degradation resulting in the
activation of the non-canonical pathway (Liao et al.,
2004).
Resolution of inflammation may also involve NF-kB
Resolution of inflammation and subsequent tissue repair
is a crucial event, and its failure is a common source of
pathology. It is believed that reversal of inflammation is
an active process that is as complex as the inflammatory
response itself, and involves numerous pathways that
are not all directly relevant to NF-kB (Serhan and
Savill, 2005). Although the traditional view of NF-kB
would lead one to imagine that it would primarily
function by being turned off during the resolution phase
of inflammation, recent work has suggested that NF-kB
also has a more active role.
During acute inflammation, there are multiple nega-
tive feedback pathways that help to rein in inflammatory
responses. It has long been known that cells such as
macrophages become resistant to repeated proinflam-
matory stimuli. BCL-3, which is induced late following
NF-jB and immunology
MS Hayden et al
6771
LPS stimulation, in combination with p50 dimers has
been shown to have a role in the inhibition of repeated
LPS responses in macrophages, a phenomenon also
referred to as LPS tolerance (Wessells et al., 2004).
Furthermore by selectively affecting chromatin remo-
deling, BCL-3 mediates repression of proinflammatory
genes, but also facilitates expression of the anti-
inflammatory gene IL-10. NF-kB p50 also appears to
negatively regulate IFNg production and proliferation
by NK cells (Tato et al., 2006).
In addition to these and other negative feedback
pathways, it was recently found that inhibition of
NF-kB during the resolution phase can prolong the
inflammatory process and prevent proper tissue repair
(Lawrence et al., 2001). It was subsequently found that
IKKa-deficient mice display increased inflammatory
responses in models of local and systemic inflammation
(Lawrence et al., 2005). Macrophages, in particular,
show increased production of proinflammatory chemo-
kines and cytokines in the absence of IKKa (Lawrence
et al., 2005; Li et al., 2005). It was suggested from these
studies that IKKa negatively regulates proinflammatory
gene expression, perhaps through mediating degrada-
tion of RelA and c-Rel following macrophage activation
by LPS.
Initiation of adaptive responses
Although innate responses alone can bring about potent
antimicrobial activities, alerting and activating the
adaptive immune system remains a crucial step for
robust and durable immune responses. This process is
largely mediated by activation and maturation of
antigen-presenting cells (APCs), which can, in turn
instruct T and B cells to carry out the adaptive response.
DC maturation mediated by pathogen recognition is
crucial for the initiation of the adaptive immune
response. To activate naı̈ve T cells, DCs must undergo
multiple changes. First, DCs must gain the ability to
interact with T cells by changing their chemokine
receptor expression and migrating into lymphoid tissues.
Second, DCs must alter their antigen processing
machinery to favor the presentation of pathogen
epitopes on MHC. Third, APCs must upregulate the
expression of costimulatory molecules B7.1/B7.2 (or
CD80/CD86), which are regulated by NF-kB and ligate
CD28 providing the second signal necessary to induce
T-cell activation. Finally, as progress is made in
exploring these events it is becoming increasingly clear
that the responses to different pathogens are tailored
based on the distribution of PRRs in different cell types
and the ability of different cell types to, in turn, interact
with T cells in a biasing manner (Iwasaki and
Medzhitov, 2004).
Maturation of DCs following viral infection depends
on nucleic acid-binding PRRs, including both TLRs and
cytoplasmic RIG family molecules. Indeed, DC matura-
tion during viral infection occurs normally in the
absence of MyD88 or TLR3, as reported previously
Oncogene
 NF-jB and immunology
MS Hayden et al
6772
(Lopez et al., 2003). Bacterial responses are either
mediated through TLRs – DCs express TLRs 1, 2, 5
and 6 – or other classes of PRRs. Murine CD8a þ DCs,
which tend to induce TH1 responses important in
clearance of viral and parasitic infections, express
TLR1, 2, 6, 9 and 11. In the absence of TLR11, for
example, mice fail to mount a TH1 response against
T. gondii, owing to the failure of CD8a þ DCs to
recognize the TLR11 ligand (Yarovinsky et al., 2005). It
remains unclear whether the ability of distinct TLR
ligands to induce TH1 versus TH2 responses is intrinsic
to the specific TLR/ligand, dose of ligand or the cell type
within which this activation occurs; evidence to date
points towards the latter. Even less clear are the roles of
other PRRs in APC maturation and the initiation of
adaptive responses.
Finally, there is the question of the role of innate
recognition of pathogens by lymphocytes themselves.
Recently, it has been suggested that TLR signaling in B
cells is also required for optimal response to certain
antigens (Pasare and Medzhitov, 2005). Both B and
T cells express TLRs, although exactly which TLRs
are expressed is debatable. At the level of mRNA
expression, human peripheral B cells express TLR1, 2, 4,
6 and 9 (Hornung et al., 2002).
Role of NF-jB in the adaptive response
AgR signaling to NF-kB
The hallmark of the adaptive immune response is
antigen specificity. In the section on hematopoiesis, we
discussed how NF-kB plays an important role in the
selection of lymphocytes bearing somatically generating
AgRs. Signaling through these antigen-specific B-cell
and T-cell receptors is therefore the central event of the
adaptive immune response. Activation of NF-kB down-
stream of BCR and TCR ligation facilitates antigen-
specific proliferation and maturation of lymphocytes
into effector cells. Signaling through these two AgRs
appears to be functionally analogous, although some of
the components utilized differ.
BCR and TCR signaling are analogous in many
aspects, in particular with respect to the activation of
NF-kB (Figure 7). The T-cell receptor complex consists

a b
Ag
Ag

TCR BCR

P
Syk Lyn
ZAP70 CARMA1 CARMA1
PDK1
P
BCL10 BCL10 P
Vav
Vav PI3K MALT1 MALT1

P TRAF6 Ras
Ras RIP2
DAG IP3
IP3
DAG
Ub AP-1
AP-1 NEMO
P
NFAT
NFAT

PP
NF- κB

Gene
Transcription

Figure 7 AgR signaling to NF-kB. Binding of TCR to peptide:MHC and co-stimulation through CD28:B7 interaction activates
NF-kB (a). Through multiple steps, initial phosphorylation events at the TCR complex lead to PI3K activation and recruitment of
PDK1. PDK1, in turn, mediates recruitment of the IKK complex through PKCy and the CARMA1 directly. PKCy phosphorylates
CARMA1 leading to the activation of IKK through BCL10, MALT1 and TRAF6. Binding to TI antigens or TD antigens in the
presence of co-stimulatory cytokines results in the activation of NF-kB through the BCR complex (b). Receptor proximal events of
BCR activation are highly analogous to those of the TCR. Although the role of PDK1 in B-cell signaling is not established, BCR
signaling to NF-kB requires PKCb as well as the CBM complex to achieve activation of IKK.

Oncogene

of a/b subunits that are associated with the CD3 protein
heterodimers g/e, d/e, and either Z/Z, Z/z or z/z, for a
total of eight membrane proteins. The BCR is, likewise,
a multiprotein complex consisting of the surface
immunoglobulin receptor associated with a heterodimer
of Iga and Igb. The AgR complexes associate with Src
family tyrosine kinases (SFKs), Lck and Fyn in T cells
and Lyn in B cells, which phosphorylate immunoreceptor
tyrosine activation motifs (ITAMs) on CD3 and Iga/b
chains. The cytoplasmic tyrosine kinases ZAP70 or Syk
are then recruited via SH2 domains to the phosphory-
lated ITAMs and initiate activation of the IP3 and Ras
family pathways. The IKK complex is rapidly recruited
to the immunological synapse and can be colocalized to
the TCR (Khoshnan et al., 2000; Weil et al., 2003). In
ZAP-70-deficient T cells, NF-kB activation can be
rescued by directly targeting a chimeric NEMO to the
immunological synapse, suggesting that signaling down-
stream of ZAP-70 may largely function for IKK
recruitment (Weil et al., 2003).
The signaling pathway from the receptor to NF-kB
requires PKCy (PKCb in B cells), CARMA1/CARD11,
BCL10 and MALT1 (Sun et al., 2000; Ruland et al.,
2001, 2003; Saijo et al., 2002; Hara et al., 2003; Ruefli-
Brasse et al., 2003;). Although there has been some
controversy, available data suggest that PKCy is largely
essential for activation of NF-kB via T-cell stimulation
(Sun et al., 2000; Pfeifhofer et al., 2003) and can mediate
the activation of IKK (Lin et al., 2000). PKCy is
specifically recruited to the immunological synapse;
although how PKCy but not other PKC isoforms is
selectively recruited remains a mystery. In B cells PKCb
is, likewise, required for recruitment of the IKK
complex to lipid rafts following BCR ligation (Su
et al., 2002). PKCy is capable of directly interacting
with the IKK complex in primary T cells (Khoshnan
et al., 2000) and might, therefore, function by bringing
IKK to the receptor complex and into proximity with
other essential components in this pathway; namely
CARMA1, BCL10 and MALT1 (collectively known as
the CBM complex). Recently, studies have provided
evidence that the protein kinase PDK1 recruits PKCy
and the IKK complex to lipid rafts. In addition, PDK1
can simultaneously recruit the CBM complex through
binding to CARMA1 (Lee et al., 2005). The induced
proximity of PKC and the CBM may allow phospho-
rylation of CARMA1 by PKCy/b (Matsumoto et al.,
2005; Sommer et al., 2005). Interestingly, T-cell-specific
PDK1 conditional deletion results in a defect in T-cell
development, preventing the production of peripheral
T cells (Hinton et al., 2004). On the other hand,
PCKy knockouts do not display defects in thymocyte
development.
The CBM complex is essential for both AgR signaling
in mature B and T cells. What is surprising however, as
mentioned above, is the lack of a role for this complex in
developing lymphocytes, and by extrapolation signaling
through the pre-AgRs. The MAGUK family protein
CARMA1 is required for activation of NF-kB in T cells
following TCR ligation, but its loss has no effect on the
development of thymocyte (Gaide et al., 2002; Egawa
NF-jB and immunology
MS Hayden et al
6773
et al., 2003; Hara et al., 2003). Similarly, BCL10 is
critical for NF-kB activation via the BCR and TCR, yet
normal numbers of peripheral T cells are seen in BCL10
knockouts, and no clear defects in B-cell development is
observed (Ruland et al., 2001). BCL10 interacts with
CARMA1 leading to BCL10 phosphorylation, although
CARMA1 lacks kinase activity (Bertin et al., 2001;
Gaide et al., 2001).
Interestingly, genetic evidence of a role for RIP2 has
recently been reported in T-cell signaling (Ruefli-Brasse
et al., 2004). RIP2 associates with BCL10 and is
necessary for TCR-induced BCL10 phosphorylation
and IKK activation. It is not yet clear how TCR
signaling regulates RIP2 and, in turn, how RIP2 might
affect IKK activity. BCL10 oligomerization has been
implicated in IKK activation through a process that
involves ubiquitination of NEMO (Zhou et al., 2004).
This ubiquitination event appears to be mediated by
MALT1, and perhaps TRAF6, although no TCR
signaling deficits have been reported in TRAF6-deficient
mice (Lomaga et al., 1999; Sun et al., 2004). If this is
true however, it is possible that the effect is mediated
through the kinase TAK1, which functions in IKK
activation downstream of TRAF6 in other pathways.
However, B cells in which TAK1 has been conditionally
inactivated have normal BCR signaling to NF-kB. More
work must be carried out with TAK1 conditional
knockouts in both the BCR and TCR pathways to
address the role of this kinase.
T-cell responses mediated by NF-kB
To become activated, naı̈ve T cells must receive two
distinct signals: antigen-specific and co-stimulatory.
Antigen-specific activation signals emanate from the
binding of the TCR to cognate antigenic peptides
presented in the binding cleft of MHC. Co-stimulatory
signaling is provided through ligation of CD28 by B7
molecules expressed on activated APCs. Stimulation of
naı̈ve T cells results in the production of IL-2, which is
necessary for their proliferation and survival. These
activated naı̈ve T cell blasts proliferate rapidly and
simultaneously undergo differentiation into effector
cells. In the case of TH cells, proliferation leads to
differentiation into immature effector cells, TH0, which
subsequently differentiate into TH1 or TH2 cells
depending on the predominant cytokine milieu. CD8 T
cells are likewise activated by professional APCs,
although they may receive secondary signals from
activated TH1 cells. The unavailability of CD8 condi-
tional knockouts, and the selective loss of CD8 cells in
the absence of NF-kB activity has prevented a thorough
characterization of the role of NF-kB in these cells.
Rapidly proliferating activated T cells rely on NF-kB
activity for protection from apoptosis as well as for the
production of cytokines supporting proliferation and
differentiation. As expected, inhibition of NF-kB in
activated T cells facilitates progression towards AICD
or apoptosis (Ivanov and Nikolic-Zugic, 1997; Jeremias
et al., 1998). Indeed, stimulation of RelA-deficient naı̈ve
T cells induces cell death (Wan and DeGregori, 2003).
Oncogene
 NF-jB and immunology
MS Hayden et al
6774
Peripheral T cells lacking c-Rel do not undergo
apoptosis, but nevertheless, fail to proliferate in
response to typical mitogenic stimuli (Köntgen et al.,
1995), and both RelA and c-Rel containing complexes
accumulate in the nucleus following TCR/CD28 stimu-
lation (Ghosh et al., 1993). Interestingly, c-Rel-deficient
T cells appear to have a defect in TH1 proliferation
and production of IFNg, indicating a selective role for
NF-kB family members in TH1/TH2 differentiation,
independent of that mediated by the innate response.
Multiple transcriptional activators and repressors
regulate expression of IL-2. Among these, members of
the NF-kB family play multiple roles. In naı̈ve T cells,
which do not express IL-2, repressive p50 homo-
dimers are found associated with the IL-2 promoter
(Grundstrom et al., 2004). Failure of T-cell proliferative
responses in c-Rel knockout mice is attributable to a
failure to produce IL-2 (Köntgen et al., 1995). In naı̈ve
T cells, c-Rel is responsible for mediating chromatin
remodeling across the IL-2 locus following CD3/CD28
co-stimulation (Rao et al., 2003). Naı̈ve T cells can be
primed by exposure to inflammatory cytokines such that
they generate a more robust response to CD3/CD28 co-
stimulation. Overexpression of an IkBa super-repressor
suggested that NF-kB is required for this priming event
in T cells (Mora et al., 2001a). More recent data indicate
that c-Rel is necessary for naı̈ve helper T-cell priming by
pro-inflammatory cytokines elicited following stimula-
tion with TLR ligands (Banerjee et al., 2005). NF-kB
RelA-containing complexes, on the other hand, appear
to function more traditionally in mediating transactiva-
tion of IL-2 gene expression, and overexpression of
RelA with c-Jun can overcome the requirement for
co-stimulation in naı̈ve T cells (Parra et al., 1998).
However, as discussed below, these complexes may also
be the targets of negative regulation following T-cell
differentiation.
Recent work in TH1/TH2 differentiation has focused
on the induction of specific transcription factors in these
two effector cell types – T-bet and GATA3, respectively.
Interestingly, mice lacking p50 are unable to mount an
asthma-like airway TH2 response, and do not induce
GATA-3 expression during T-cell stimulation under
TH2 differentiating conditions (Das et al., 2001).
Consistent with this finding, BCL-3-deficient T cells
also fail to undergo TH2 differentiation. Furthermore,
BCL-3 can induce expression of a reporter gene from a
gata-3 promoter, suggesting that p50/BCL-3 complexes
are crucial for TH2 differentiation (Corn et al., 2005).
Conversely, the same authors found that RelB-deficient
T cells are deficient in TH1 differentiation and IFNg
production, and show decreased expression of T-bet;
likely through a failure to upregulate STAT4, which
functions in signaling from IFN to T-bet induction.
Therefore, it appears that NF-kB activation during
TCR stimulation may render cells competent for both
proliferative and differentiating stimuli.
As TH cells differentiate into TH1 or TH2, they
decrease their expression of IL-2 and, instead, become
dependent on TH1 and TH2 cytokines (e.g., IFNg and
IL-4). As a corollary, NF-kB transactivation of the IL-2
Oncogene
gene is repressed. Direct binding of T-bet to p65 that is
associated with the IL-2 gene enhancer may mediate the
repression of IL-2 production in TH1 cells (Hwang et al.,
2005). Alternatively, in TH2 cells the lack of IL-2
transcription may be due to the decreased levels of RelA
activation in TH2 cells (Lederer et al., 1994).
B-cell responses mediated by NF-kB
B-cell responses can be classified into two groups:
thymus-dependent (TD) or thymus-independent (TI).
In response to T-dependent antigens, B cells require co-
stimulatory signaling from TH cells expressing CD40L
and cytokines, such as IL-4. B cells from individuals
with a mutation in CD40L are unable to undergo class
switch recombination in response to T-dependent
antigens (Aruffo et al., 1993). Signaling through CD40
activates both canonical and non-canonical NF-kB
pathways, although it is unclear which is operative in
the response to T-dependent antigens. For example,
whereas B cells from p52
/
mice mount inadequate
humoral responses to various T-dependent antigens,
they exhibit a normal response following adoptive
transfer into rag-1
/
mice – indicating that this deficit
is not intrinsic to B cells (Franzoso et al., 1998).
Furthermore, B cells from relB
/
mice, although
crippled in their proliferative response, undergo normal
IgM secretion and class switching in response to various
stimuli (Snapper et al., 1996a). Therefore, non-canonical
NF-kB pathway activation downstream of CD40 is
probably not required for class switching during
T-dependent antigen responses.
Analysis of the canonical NF-kB pathway is compli-
cated by more generalized defects in lymphocyte
response owing to the requirement for this pathway in
AgR signaling. Nevertheless, whether downstream of
CD40 or other stimuli, evidence supports canonical
pathway activation in the process of class switch
recombination. Following adoptive transfer, B cells
from rela
/
mice exhibit markedly diminished class
switching, despite a modest loss of lymphocyte proli-
feration following various stimuli (Doi et al., 1997).
Likewise, c-Rel-deficient mice, or mice lacking the c-Rel
C-terminal transactivation domain, fail to generate a
productive humoral immune response suggesting a
requirement for c-Rel in class switch recombination
(Köntgen et al., 1995; Zelazowski et al., 1997; Carrasco
et al., 1998). B cells from nfkb1
/
mice exhibit decreased
proliferation in response to mitogenic stimulation, and
p50/RelA double knockout B cells exhibit greater
defects in proliferation and class switching (Snapper
et al., 1996b; Horwitz et al., 1999). Therefore, analyses
of knockout animals suggest that the canonical NF-kB
pathway likely has a role in maturation of the B-cell
response in addition to directly mediating proliferative
responses following BCR ligation.
As discussed above, signaling through TLRs has an
important role in the initiation of the adaptive immune
response via APCs of the innate immune system. In
recent years, however, there has also been increasing
interest in the ability of TLR signaling to directly

modulate the adaptive response. For example, it has
been observed that homeostatic polyclonal activation of
B cells, which results in the so-called serological
memory, that is, detectable antibody to antigens that
are no longer present in the host, can be induced/
maintained by TLR ligation (Bernasconi et al., 2002).
Analogously, TLR2 is upregulated in CD4 þ T cells
following TCR stimulation, and TLR2 ligands
may thus provide an activation/maintenance signal in
these cells (Komai-Koma et al., 2004). That signaling
through TLRs in these aspects of B-cell responses
requires NF-kB seems likely, but has yet to be
demonstrated.
TI antigens have an intrinsic ability to activate B-cell
responses in the absence of T-cell help by acting as B-cell
mitogens, for example by acting as TLR ligands or by
binding with high avidity to the BCR through repetitive
structural features. In such cases, it is expected that B-cell
responses are more dependent on members of the
canonical pathway that have well-documented roles in
TLR signaling, or BCR signaling (as discussed above).
For example, c-Rel-deficient B cells are highly sensitive
to apoptosis following BCR cross-linking (Grumont
et al., 1998, 1999; Owyang et al., 2001). As mentioned
above, p50 and p50/pRelA double knockout B cells are
deficient in responses to TI stimulation. Likewise,
IKKb-deficient B cells fail to mount TI or TD responses
(Li et al., 2003). These IKKb-deficient B cells also
exhibit increased spontaneous apoptosis, suggesting that
NF-kB is important in survival of B cells.
Maintenance and memory: a role for NF-kB in lymphoid
cell survival
Lymphocyte homeostasis is dependent on the survival of
mature lymphocytes in addition to replenishment of the
peripheral lymphocyte pool through lymphopoiesis.
Consequently, there is increasing interest in the possible
role of NF-kB in the survival of mature lymphocytes. It
is widely accepted that lymphocyte survival is mediated
through tonic stimulation downstream of the AgR, as
well as certain cytokine receptors. As discussed above,
genetic targeting experiments support an important role
for NF-kB family members in lymphocyte survival.
Naı̈ve T cells require continued contact with MHC:self-
peptides, most likely expressed on lymphoid DCs, to
generate the tonic TCR signal that is essential for
continued survival. Survival of memory cells, on the
other hand, is independent of continued contact with
self-peptide:MHC complexes.
B cells are formed at a far higher rate than T cells and
therefore B cells also undergo a significantly higher rate
of turnover. Nonetheless, B cells too require mainte-
nance signals to achieve peripheral homeostasis. The
AgR on B cells most likely provides a basal level of
signaling, albeit independent of the presence of antigen,
which is required for maintenance of mature B cells. Not
surprisingly, B cells from RelA
/
, p100
/
, p105
/
and
c-Rel
/
mice display increased sensitivity to apoptosis
and/or decreased survival ex vivo (Grumont et al., 1998;
Claudio et al., 2002; Prendes et al., 2003).
NF-jB and immunology
MS Hayden et al
6775
In large part, these defects appear to be due to a loss
of BCR signaling, as demonstrated in an elegant study
that demonstrated that deletion of the BCR from
mature B cells led to a complete loss of the peripheral
B-cell pool (Kraus et al., 2004). Most likely this was due
to the loss of signaling to NF-kB in these cells because
loss of IKKb, NEMO or components of the CBM
complex in mature B cells also results in a complete loss
of peripheral B cells (Pasparakis et al., 2002; Li et al.,
2003; Thome, 2004).
The non-canonical NF-kB pathway is also relevant to
B-cell survival, as the loss of IKKa results in striking
defects in B-cell survival (Kaisho et al., 2001; Senftleben
et al., 2001a). However, rather than acting downstream
of tonic BCR signaling, recent studies have implicated
signaling from BAFFR in this aspect of the B
lymphocyte survival (reviewed in Mackay et al., 2003).
Together, these data suggest that a subset of Bcl-2
family members, for example, the antiapoptotic factor
A1, are regulated by p52/RelB-containing complexes
and are necessary for the maintenance of mature B cells.
Concluding remarks
NF-kB was originally described as a transcriptional
regulator in the adaptive immune response; however,
subsequent studies have revealed its importance in
hematopoiesis, lymphoid organogenesis and innate
immunity. Investigations of mice with targeted deletions
and mutations have shed considerable light on the role
of NF-kB in lymphoid organogenesis. For example,
characterization of the aly/aly mouse in part led to the
discovery of the non-canonical NF-kB pathway and its
role in organogenesis. Progress continues to be made in
understanding AgR signaling to NF-kB, and this work
has led to the appreciation of regulatory ubiquitination
events in IKK activation (see reviews by Perkins, 2006;
Scheidereit, 2006). The specificity of the requirement for
the CBM complex and PKCy/b in signaling by T-cell
and B-cell receptors opens the door to the development
of equally specific NF-kB inhibitors. However, there
remain fundamental gaps in our understanding of how
these components mediate IKK activation and the
possible role of regulatory ubiquitination in this process.
The role of NF-kB in hematopoiesis remains partially
defined, although there is little doubt about its
importance. Genetic targeting in mice has allowed the
enumeration of multiple steps in hematopoiesis at which
various NF-kB pathway components are required;
however, a cohesive picture of how NF-kB functions
in these steps remains elusive. For example, whereas we
know that canonical NF-kB activity is required in early
lymphopoiesis, it is unclear whether this is in the
regulation of TNFa production or in mediating a
survival signal in the developing lymphocyte. NF-kB is
required in the process of positive and negative
selection, but again, its mechanism(s) of action remains
poorly defined. Progress using in vitro systems for
studying lymphocyte development may allow a more
Oncogene
 NF-jB and immunology
MS Hayden et al
6776
rigorous assessment of NF-kB function in these
processes. Likewise, advances in conditional gene
targeting approaches and the generation of animals in
which defective versions of NF-kB genes have been
knocked-in may help to overcome the problems of
embryonic lethality and functional redundancy that
have sometimes made existing studies difficult to
interpret.
T- and B-cell responses require NF-kB as a prosurvi-
val factor as well as for the regulation of genes involved
in differentiation to effector cells. More recently, a
limited number of studies have suggested a role for
PRRs in lymphocyte activation, and the role of NF-kB
in this process remains to be elucidated. The role of
NF-kB in the differentiation of TH cells is incompletely
understood, and requires further clarification. We also
know very little about the role of NF-kB in CD8 þ
activation, differentiation and function; progress in this
area awaits development of better tools for genetically
manipulating this cell population. Upon successful
clearance of pathogen, regulation of NF-kB allows
resolution of the response and facilitates the develop-
ment of memory cells. To date, relatively little is known
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