news and v iews

Skin function for human CD1a-reactive T cells

Marco Colonna
Human CD4+ T cells that produce interleukin 22 are an essential component of skin defense and repair. New
evidence shows that these T cells recognize CD1a-lipid complexes on Langerhans cells.
he skin provides an efficient barrier that
protects the organism from physical and
chemical attack, as well as from the invasion
of pathogens. Permeating both the outer
and inner layers (epidermis and dermis), the
immune system promotes integrity of the
skin. Langerhans cells (LCs), dermal dendritic
cells (DCs), plasmacytoid DCs, mast cells
and T cells detect skin damage and initiate
innate responses as well as T cell and Bcell
responses1. In addition, the immune system is
actively involved in the production of factors
that promote repair of the epidermis2, including fibroblast growth factor, insulin-like growth
factor 1 and interleukin 22 (IL-22). IL-22 acts
directly on keratinocytes, inducing the release
of antimicrobial peptides as well as survival and
proliferation3. Several groups have shown that
T cells provide an important source of IL-22
in the skin47. However, the origin, differentiation pathway and restriction elements of the
T cells responsible for secreting IL-22 in
the skin have remained unknown. In this issue
of Nature Immunology, Moody and colleagues
report the remarkable discovery that these
T cells respond to CD1a8, a cell surface mole
cule expressed on human LCs that presents
endogenous lipids to T cells. These results demonstrate for the first time that lipid antigens
induce an IL-22 response in the skin (Fig. 1).
The CD1 cell surface glycoproteins include
CD1d, which functions similarly in humans
and mice, as well as CD1a, CD1b and CD1c,
which are present in humans but absent from
mice. The CD1 molecules, which are expressed
on antigen-presenting cells, bind endogenous
and exogenous lipids and present them to
T cells, inducing their population expansion
and differentiation9,10. CD1-restricted T cells
can detect changes in cellular lipid content that
may occur during infection, cancer or autoimmunity. The CD1 molecules are heterogeneous
in terms of structure, expression, mechanisms
of lipid sampling, the type of lipids they present on the cell surface and the types of T cells
they induce. Much attention has been given to
the effect of lipid presentation by CD1d on the
Marco Colonna is in the Department of Pathology
and Immunology, Washington University School of
Medicine, St. Louis, Missouri, USA.
e-mail: mcolonna@wustl.edu

Epidermis

LC
IL-22
CD1a-lipid
bTCR
IL-23?

Costimuli?

Dermis

DDC

IL-22

CD4+ T cell

IL-2
CCR4

Blood

CD4+ T cell
RA

IFN-

CCR10
CCR6

CD4+ T cell

CD4+ T cell
RO

Marina Corral

2010 Nature America, Inc. All rights reserved.

Figure 1 CD1-reactive CD4+ T cells. LCs express a cell surface CD1a-lipid complex that stimulates
CD1a-reactive CD4+ T cells. The stimulation probably occurs at the epidermis-dermis junction. However,
CD1a is also expressed on certain dermal DCs (DDC). It is not known whether T cell activation also requires
costimulatory signals and/or cytokine signals, such as IL-23. Activated T cells secrete IL-22, which acts on
keratinocytes, promoting the production of antimicrobial peptides, survival and proliferation. Some CD1areactive T cells are polyfunctional and produce interferon- (IFN-) and IL-2. CD1a-reactive T cells can
represent a noticeable percentage of peripheral blood T cells. The chemokine receptors CCR4, CCR6 and
CCR10 drive the migration of CD1a-reactive T cells into the skin. RA, naive T cell; RO, memory T cell.

T cell repertoire. CD1d induces the differentiation of a unique subset of T cells, known as natural
killer T cells, most of which display an invariant
T cell antigen receptor (TCR) -chain11,12. The
functional characterization of CD1d was facilitated by the early identification of a high-affinity
exogenous lipid ligand, -galactosyl ceramide.
This allowed the synthesis of -galactosyl ceramideCD1d tetramers, which can be used to
track natural killer T cells. In addition, knockout mouse models in which CD1d and invariant natural killer Tcells are deleted have been
generated for invivo studies.
For many reasons, understanding of T cell
responses to CD1a, CD1b and CD1c has lagged
behind that of responses to CD1d. Because these
molecules are absent from mice, generating
knockout models has not been feasible. Tcells
restricted by CD1a, CD1b and CD1c also seem to
express diverse TCRs, which makes them much
more difficult to track. Although lipid ligands for

nature immunology volume 11 number 12 DECEMBER 2010

CD1a, CD1b and CD1c have been identified13,14,

they are not optimal for the generation of highavidity tetramers that could be used to effectively
identify restricted T cells in a T cell population.
Therefore, knowledge of T cell responses induced
by CD1a, CD1b and CD1c has been based on T
cell clones established from human donors.
To systematically probe the human T cell repertoire for cells that respond to CD1a, CD1b and
CD1c, Moody and colleagues developed a clever
approach that bypasses the need for CD1-lipid
tetramers8. They elicited T cell responses with
nonprofessional antigen-presenting cells of the
erythroleukemia cell line K562, transfected with
genes encoding CD1a, CD1b or CD1c. K562
cells express no major histocompatibility complex (MHC) class II and little MHC class I, which
allows the stimulation of MHC-unrelated donors
without the induction of conventional alloreactive T cells. With this approach, they found
that all donors tested had an unexpectedly high
1079

 2010 Nature America, Inc. All rights reserved.

news and v iews

frequency of T cells that responded to K562 cells
transfected with the gene encoding CD1aup to
1 in 50 Tcells in the blood. In contrast, only a few
donors had CD1b- or CD1c-restricted T cells.
Clonal analysis of CD1a-reactive T cells
shows a diverse TCR repertoire, which suggests
recognition of disparate lipids. Additionally,
the CD1a-reactive T cells have a memory-type
phenotype and express CD4 as coreceptor. It
is well known that CD4+ T cells differentiate
into distinct subsets, including the T helper
type 1 (TH1) and TH2 subsets and the IL-17producing helper T cell (TH17) subset, that produce restricted patterns of cytokines tailored to
fight various microbial pathogens. To determine
which subset the CD1a-reactive T cells might fit
into, Moody and colleagues assess cytokine secretion and find that these T cells preferentially
produce IL-22 (Fig. 1). Although TH17 cells were
originally thought to be the main producers of
IL-22, subsequent studies have shown the existence of a CD4+ helper T cell subset that preferentially secretes IL-22 but not IL-17 (refs. 47).
These T cells, known as TH22 cells, express cutaneous lymphocyte antigen and the chemokine
receptors CCR10, CCR6 and CCR4, which direct
them toward the skin. Remarkably, the CD1areactive CD4+ T cells also express CCR10, CCR6
and CCR4 and do not produce IL-17 (Fig. 1).
Therefore, CD1a-reactive CD4+ T cells probably
correspond to TH22 cells or at least constitute a
substantial proportion of these cells.
What are the physiological CD1a+ antigenpresenting cells that present lipids and induce
TH22 priming and activation? In the skin, CD1a
has high expression on LCs, which form a contiguous network in the epidermis. Thus, LCs
may have a substantial role in the activation

of TH22 cells. Consistent with that, Moody

and colleagues found that CD1a-reactive T cell
clones responded to LCs isolated from the
epidermal sheets of human skin8 (Fig. 1). As
CD1a has also been found on some dermal
DCs and dermal macrophages15, these cells
may also contribute to the activation of TH22
cells. In addition, CD1a is expressed on cortical
thymocytes, which suggests the possibility that
TH22 cells may originate in the thymus through
a process of positive selection mediated by lowavidity CD1aendogenous lipid complexes. In
addition to requiring CD1a, the differentiation
and/or activation of TH22 cells may require additional signals, such as IL-23, which is a strong
inducer of IL-22 in innate lymphocytes16.
The role of CD1alipid antigen complexes
in activating T cell responses in the skin probably affects not only skin homeostasis but also
skin pathology. The epidermis is rich in lipids
that protect the skin barrier. These lipids may be
captured by LCs and may be presented on CD1a
to induce the homeostatic proliferation of TH22
cells. However, changes in lipid composition due
to physical and chemical damage, pathogenic
invasion and inflammation may cause activation of TH22 cells. Either excessive stimulation or
altered thymic or peripheral education of CD1areactive T cells may generate TH22 cells responsive to endogenous lipids. This is a possible
scenario in psoriasis, a chronic T cellmediated
disease of the skin that is caused in part by excessive secretion of IL-22 in the skin and thus could
potentially be treated with IL-22 blockers3.
In mice, skin-resident T cells consist mainly of
a unique subset of T cells that depend on the
cell surface molecule Skint1 for their development1; this T cell subset and Skint1 are absent

from humans. It is now known that CD1a, which

has no mouse counterpart, is crucial for the activation of human TH22 cells. Thus, humans and
mice seem to have evolved different strategies for
generating immune responses in the skin, which
perhaps reflects differences in physiology and the
types of harmful agents to which humans and
mice are exposed. The investigation of human
CD1a-reactive T cells will be of particular importance to gain insight into the mechanisms of skin
diseases, including infection, atopic dermatitis
and psoriasis, and to identify potential avenues
for therapeutic intervention.
COMPETING FINANCIAL INTERESTS
The author declares no competing financial interests.
1. Strid, J., Tigelaar, R.E. & Hayday, A.C. Semin.
Immunol. 21, 110120 (2009).
2. Havran, W.L. & Jameson, J.M. J. Immunol. 184,
54235428 (2010).
3. Witte, E., Witte, K., Warszawska, K., Sabat, R. & Wolk, K.
Cytokine Growth Factor Rev. published online,
doi:10.1016/j.cytogfr.2010.08.002 (25 September
2010).
4. Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A. &
Sallusto, F. Nat. Immunol. 10, 857863 (2009).
5. Eyerich, S. et al. J. Clin. Invest. 119, 35733585 (2009).
6. Fujita, H. et al. Proc. Natl. Acad. Sci. USA 106,
2179521800 (2009).
7. Trifari, S., Kaplan, C.D., Tran, E.H., Crellin, N.K. &
Spits, H. Nat. Immunol. 10, 864871 (2009).
8. de Jong, A. et al. Nat. Immunol. 11, 11021109 (2010).
9. Cohen, N.R., Garg, S. & Brenner, M.B. Adv. Immunol.
102, 194 (2009).
10. Silk, J.D., Salio, M., Brown, J., Jones, E.Y. & Cerundolo, V.
Annu. Rev. Cell Dev. Biol. 24, 369395 (2008).
11. Kronenberg, M. & Kinjo, Y. Curr. Opin. Immunol. 21,
391396 (2009).
12. Bendelac, A., Savage, P.B. & Teyton, L. Annu. Rev.
Immunol. 25, 297336 (2007).
13. Moody, D.B. Adv. Immunol. 89, 87139 (2006).
14. De Libero, G., Collmann, A. & Mori, L. Eur. J. Immunol.
39, 26482656 (2009).
15. Klechevsky, E. et al. Immunity 29, 497510 (2008).
16. Cua, D.J. & Tato, C.M. Nat. Rev. Immunol. 10,
479489 (2010).

More things in heaven and earth: defining innate and

adaptive immunity
Christine A Biron
Natural killer cells have emerged as key components of innate immunity with critical antimicrobial functions. New
work showing that they can also be accessed by vaccination to deliver antigen-specific memory responses and protect
against subsequent viral infections challenges the traditional distinctions made between innate and adaptive immunity.

here are many examples in immunology of

the assignment of names before function
is thoroughly understood. As a result, the
Christine A. Biron is in the Department of Molecular
Microbiology and Immunology, Brown University,
Providence, Rhode Island, USA.
e-mail: christine_biron@brown.edu

1080

words or their definitions can get in the way

of the fields ability to incorporate radical new
information. Innate immunity is defined as
being dependent on germline genes, present at
all times and functional during early primary
infections but not increasing with repeated
exposures. In contrast, adaptive immunity
has been characterized as being dependent on

rearrangement of genes, antigen specific and

requiring time for induction during primary
challenges. Adaptive memory lymphocytes,
stimulated during primary responses, including those elicited by vaccination, are long lived
and deliver heightened antigen-specific recall
responses after secondary exposure. There
are, however, new experimental approaches

volume 11 number 12 DECEMBER 2010 nature immunology