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T cell effector functions: a blend of innate programming and acquired plasticity

Marc Bonneville*, Rebecca L. OBrien and Willi K. Born

Abstract | T cells have several innate cell-like features that allow their early activation following recognition of conserved stress-induced ligands. Here we review recent observations revealing the ability of T cells to rapidly produce cytokines that regulate pathogen clearance, inflammation and tissue homeostasis in response to tissue stress. These studies provide insights into how they acquire these properties, through both developmental programming in the thymus and functional polarization in the periphery. Innate features of T cells underlie their non-redundant role in several physiopathological contexts and are therefore being exploited in the design of new immunotherapeutic approaches.
Pattern recognition receptor
(PRR). A host receptor (such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs)) that can sense pathogenassociated molecular patterns and initiate signalling cascades that lead to an innate immune response. These can be membrane bound (such as TLRs) or soluble cytoplasmic receptors (such as retinoic acid-inducible gene I (RIG-I), melanoma differentiationassociated gene 5 (MDA5) and NLRs).

*Institut National de la Sant et de la Recherche Mdicale (INSERM) U892, IRT UN, 8 quai Moncousu, BP 70721, 44007 Nantes cedex 1, France. Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, Colorado 80206, USA. Correspondence to M.B. or W.K.B. emails: bonnevil@nantes. inserm.fr; born@njhealth.org doi:10.1038/nri2781 Published online 11 June 2010

The integrity of higher vertebrates is maintained through protective mechanisms that can detect stress-induced determinants that arise following infection, injury or cellular alterations. This surveillance involves both innate and adaptive immune processes. Innate responses, mainly mediated by natural killer (NK) cells and myelomonocytic cells, are readily activated following engagement of non-clonal receptors referred to as pattern recognition receptors (PRRs), which are specific for determinants that are broadly expressed by microorganisms or are upregulated by host cells in response to cell stress1,2. PRR engagement triggers an inflammatory response that initially leads to increased microbicidal and cytotoxic functions of immune cells, and clearance of the eliciting agent, and later to tissue repair and immune downmodulation3. Adaptive immune cells have overall functions that are similar to those of innate cells but, owing to immunological memory, they can yield stronger and faster responses after repeated exposure to a given eliciting agent 4. The establishment of immunological memory implies expansion of T and B cells, specific for the eliciting antigen, after engagement of clonally distributed T cell receptors (TCRs) and B cell receptors (BCRs). Clonally expanded T and B cell populations acquire a restricted set of effector functions that are presumably best suited for clearance of the eliciting agent at a given time point in a given tissue. Innate cells are involved in the induction of adaptive immune responses of appropriate strength, kinetics and function in two ways. First, they efficiently internalize pathogens and dying cells and process them into peptide antigens that are presented in the context of MHC

molecules to conventional T cells. Second, they integrate danger and inflammatory cues and translate them into stimuli that lead to proper functional polarization of T cell and B cell responses4. Although, generally, innate immune responses precede adaptive immune responses, a reverse interplay from adaptive to innate immune effectors also contributes to the early recruitment and activation of innate immune cells and subsequent functional polarization of MHC-restricted T cells. T cells contributing to this reverse crosstalk involve subsets of T cells restricted by the non-polymorphic MHC class I-like molecules CD1d and MHC-related protein 1 (MR1) (known as invariant NKT cells and mucosa-associated invariant T cells, respectively), as well as T cells expressing TCRs5,6. These lymphocytes have been termed non-conventional, innate-like or transitional T cells, owing to several distinguishing features that are shared with innate immune cells5,7. Similar to other non-conventional T cells, T cells recognize conserved non-peptide antigens that are upregulated by stressed cells, the expression modalities and distribution of which resemble those of pathogenassociated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) recognized by PRRs. These cells acquire a pre-activated phenotype associated with the upregulation of memory markers early in their development. This pre-activated status allows rapid induction of effector functions following the detection of tissue stress. Another important feature of T cells is their tropism for epithelial surfaces, such as those of the liver and skin, and mucosae from respiratory, digestive and reproductive
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Conventional T cell
A T cell subset specific for peptide antigens that are presented by polymorphic MHC class I molecules (HLA-A, HLA-B, HLA-C in humans, H2K, H2D, H2L in mice) or MHC class II molecules (HLA-DP, HLA-DQ, HLA-DR in humans, IE or IA in mice).

organs, to where they migrate early in their development and persist as resident cells. Interestingly, they frequently express invariant or closely related TCRs in a given tissue site, which differ from one tissue to another, reflecting homogeneous, but distinct, antigen recognition repertoires from one tissue to another (BOX 1). The physiological roles fulfilled by T cells are varied and include protective immunity against extracellular and intracellular pathogens, tumour surveillance, modulation of innate and adaptive immune responses, tissue healing and epithelial cell maintenance, and regulation of physiological organ function5,7. Their contribution to many of these physiopathological processes has been revealed by analysis of mice deficient for individual T cell subsets. As suggested by recent observations that are reviewed here, the non-redundant role of T cells in various physiopathological processes relies on a combination of antigen specificity, tissue distribution and functional properties rather than on any of these individually. These studies provide new insight into the coordinated acquisition of a restricted set of TCRs, tissue homing and effector functions early during T cell development that give rise to T cell responses with appropriate kinetic, spatial and functional characteristics. In addition to this innate programming, specialized subsets of

T cells retain functional plasticity in the periphery, which allows them to exert distinct effector functions depending on the inflammatory context and the receptors that are engaged. Here we propose mechanisms explaining how T cell functional specialization and plasticity account for their interplay with immune and non-immune partner cells. Improved understanding of such cellular interplays has been recently exploited in the design of innovative immunotherapeutic approaches targeting T cells in humans.

Activation and functional attributes of T cells The expansion and functional differentiation of MHCrestricted T cells requires concomitant engagement of the TCR and co-stimulatory receptors that function together to generate signals of appropriate strength, duration and quality. DAMPs are sensed by co-stimulatory receptors, the engagement of which determines whether a naive T cell precursor will expand and differentiate into effector cells. In the case of T cells, the detection of stress-induced molecules is achieved by both TCR and non-TCR molecules (such as Toll-like receptors (TlRs) and natural killer receptors (NKRs)) that act separately, synergistically or additively to activate particular T cell effector functions (FIG. 1).
Sensing of cell stress and infection through TCRs. we know little about the specificity and antigen recognition modalities of TCRs. As recently reviewed8, several ligands that interact with TCRs are MHC molecules or MHC-related molecules (such as the mouse T10 and T22 molecules or the human CD1c molecules). TCRs also bind to MHC-unrelated molecules, such as viral glycoproteins9 or heteromeric ATPase complexes10. Binding to these MHC-unrelated molecules might reflect fortuitous crossreactivity of TCRs that also bind MHC-related molecules or physiological recognition of heterogeneous determinants, as suggested by the unusual immunoglobulin-like antigen recognition mode of TCRs shown by recent structural studies11. Irrespective of the exact specificity of TCRs, all of their ligands described so far are markedly upregulated in response to cellular infection or dysregulation. This DAMP-like characteristic is also seemingly shared by other yet undefined TCR ligands. For example, binding studies using recombinant TCRs derived from mouse invariant v6v1+ and v1v6.3+ T cells indicate rapid upregulation of their respective ligands on peritoneal macrophages following infection with Listeria monocytogenes and upregulation of v6v1 TCR ligands following TlR signalling 12. An interesting example of recognition of both stress-induced molecules and PAMPs is provided by human v9v2+ T cells, which are activated by isoprenoid pathway metabolites known as phosphoantigens1315. Human v9v2+ T cells can be activated by very small amounts (<1 nM) of phosphoantigen that are produced through the isoprenoid pathway that operates in many microorganisms, but these T cells are 1,000-fold less sensitive to phosphoantigens that are produced through the mevalonate pathway in mammalian cells1315. This allows efficient detection by human v9v2+ T cells of infected tissues producing minute

Box 1 | Frequency, distribution and repertoire of T cells

T cells arise before T cells during thymic ontogeny and predominate at early stages (day 14 to day 18 after conception in mice) of fetal development (reviewed in REFs 128,129). They make up a minor fraction of rodent and human thymocytes and T cells in the spleen, lymph nodes and peripheral blood after birth, but are greatly enriched in epithelial tissues, such as the epidermis and mucosa of the digestive and reproductive tracts. Similar to B cell receptors and T cell receptors (TCRs), TCRs are generated through somatic rearrangement of V (variable), D (diversity) and J (joining) gene segments. Structural diversity of TCRs depends on both combinatorial usage of different sets of V, D and J segments and junctional diversification processes associated with the addition or loss of variable numbers of nucleotides at the VJ, VD or DJ junctions. Although, theoretically, approximately 1016 distinct TCRs can be produced in rodents or humans, the set of TCRs detected on peripheral T cells is far more limited. Individual T cell subsets in particular tissue locations show biased use of certain TCR V gene segments and, in some cases, express invariant TCRs with identical (canonical) junctional sequences (see the table). These invariant T cell subsets are derived from early waves of fetal thymocytes, unlike peripheral subsets that express more diverse TCRs. Throughout this Review, we use the TCR nomenclature of Heilig and Tonegawa130 for rodent T cells and Lefranc and Rabbitts131 for human T cells.


Peripheral location
Adult thymus Spleen Lymph nodes Epidermis Liver Gut epithelia Uterovaginal epithelia Lung epithelia Thymus Peripheral blood Spleen Liver Gut epithelia Dermis

Predominant V gene segment usage

Diverse V1 and V4 Diverse V5V1 V1V6.3, V4 and V6 V7V4, V7V5 and V7V6 V6V1 V4 and V6 V1 V9V2 V1 V1 and V3 V1 and V3 V1

V(D)J diversity
High High High Invariant Intermediate Intermediate Invariant Intermediate High Intermediate High High High High


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Stress-induced NKR ligands, such as RAE1, MICA, MICB and ULBPs NKG2D

Target cell

T cell Cytotoxicity

Inflammation, DNA damage, oncogenesis and infections DAMPs and PAMPs


Proliferation, cytokine release, immunoregulation and cytoprotection Inflammation (IL-17 and IFN) Dectin 1


Stress-induced TCR ligands such as CD1c, T10 and T22 Microbial and endogenous phosphoantigens

Figure 1 | Sensing of cellular stress and infection by T cells. T cells can recognize separately, additively or synergistically three sets of stress-inducedImmunology stimuli: Nature Reviews | MHC-related and -unrelated T cell receptor (TCR) ligands (such as the weakly polymorphic MHC class I-like human CD1c molecules and mouse T10 and T22 molecules, and microbial and endogenous phosphoantigens), various cell surface molecules (such as retinoic acid early transcript 1 (RAE1) and MHC class I polypeptide-related sequence A (MICA)) that engage the activating natural killer receptors (NKRs) such as NK group 2, member D (NKG2D), and/or danger-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) recognized by pattern recognition receptors (such as Toll-like receptors (TLRs) and dectin 1). IFN, interferon-; IL-17, interleukin-17; ULBP, cytomegalovirus UL16-binding protein.

epithelial tumours21 or by human v9v2+ T cells against virus-infected targets22 without concomitant TCR engagement. The mechanisms underlying TCRdependent versus TCR-independent NKG2D activation are still unclear, but they probably depend on the tissue context of T cell activation and the degree of prior exposure of the cells to inflammatory cytokines23. In addition to NKRs, the engagement of TlRs and NOD-like receptors by PAMPs triggers early inflammatory responses mediated by innate cells and nonconventional T cells, including T cells. In particular, interactions between extracellular bacteria and PRRs (such as TlR2 and dectin 1 (also known as CleC7A)) expressed by mouse v6v1+ cells probably contribute to their early activation in intraperitoneal infection models24,25. More commonly, activation of T cell responses by PAMPs is indirect, involving TlR-induced release of pro-inflammatory cytokines by dendritic cells (DCs). Similar to NK cells and invariant NKT cells2628, such indirect activation, which can be achieved with or without concomitant engagement of the TCR or NKRs, leads to early induction of interferon- (IFN) production through a positive feedback loop involving interleukin-12 (Il-12)29,30 or type I IFNs31. PAMPs can also indirectly trigger Il-17 production by mouse v6v1+ T cells, through the induction of Il-23 production by DCs after co-engagement of TlR2 and NlRs24,25. Activation kinetics. The rapid activation of T cells occurs owing to qualitative and quantitative features. Several T cell subsets have a memory and preactivated phenotype in naive individuals, either as a consequence of intrathymic developmental programming (see later) or postnatal peripheral stimulation by environmental or stress-induced ligands (for example, in the case of human v9v2+ T cells32). Moreover, the high frequency of pre-existing T cells that can respond to a given challenge also enables responses to occur rapidly, without the need for prior selection and expansion. In this regard, interactions between TCRs and stress-induced ligands involve recurrent germline motifs that are shared by a large fraction of non-selected TCRs8, which, in the case of recognition of T10 or T22 by mouse T cells, contribute to most of the ligandTCR binding energy 33. This mechanism bypasses the need for amplification of lymphocytes with the relevant specificity through thymic selection or peripheral antigen-driven processes. Finally, the expression of different homing receptors by developing thymocytes with distinct TCR repertoires further enhances the frequency of T cells with a given antigen specificity in a given tissue and enables their rapid activation in response to cell stress. Effector functions. T cells have a broad array of effector functions that reflect their involvement in diverse physiopathological processes. They can kill infected, activated or transformed cells, through pathways that involve the engagement of death-inducing receptors, such as CD95 (also known as FAS) and TNF-related apoptosis-inducing ligand receptors (TRAIlR), and the release of cytotoxic
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Invariant NKT cell

(iNKT cell). Lymphocytes that express a particular variable gene segment, V14 (in mice) and V24 (in humans), precisely rearranged to a particular J gene segment to yield T cell receptor -chains with an invariant sequence. Typically, these cells express memory T cell markers and NK cell receptors, are enriched in the liver, are activated by recognition of CD1d (particularly when bound with -galactosylceramide) and readily produce IL-2, IL-4, IL-13 and IFN.

amounts of microbial phosphoantigens and prevents them from being activated by normal tissue cells that express basal levels of the weakly stimulatory mammalian metabolites. when mammalian cells are activated or undergo transformation, phosphoantigens are highly upregulated to levels that are sufficient to activate v9v2+ T cells, supporting their role in the recognition of both cell stress and infection. The modalities of phosphoantigen-mediated stimulation of human v9v2+ T cells remain unknown but possibly involve cell surface receptors with known affinity for phosphorylated substrates, such as the recently identified ecto-F1 ATP synthase complex 10. Dual recognition of stress and infection is also achieved by human v1+ T cells, as many of them react in a TCR-dependent manner against both epithelial cell-derived tumours and cells infected by common herpesviruses16. Sensing of cell stress and infection through other receptors. The detection of stress by T cells also involves non-clonal receptors, such as TlRs and NKRs, that are upregulated following functional differentiation of memory T cells. As recently reviewed17, T cell responses to tumour and infected cells are fine-tuned by activating and inhibitory immunoglobulin-like or lectin-like NKRs. The activating receptor natural killer group 2, member D (NKG2D) has a key role in these processes owing to its broad expression by T cells and its reactivity against conserved MHC-related ligands that are upregulated by transformed or infected cells18. NKG2D generally functions synergistically with the TCR as a costimulator 19,20, but it can also trigger cytotoxic responses by intraepidermal mouse v5v1 + T cells against

Mucosa-associated invariant T cell

(MAIT cell). A conserved mammalian T cell subset expressing TCR -chains with a canonical V7.2 junctional sequence in rodents and humans. MAIT cells are specific for an as yet undefined antigen that is bound to the monomorphic MHC class I-related MR1 product. similar to iNKT cells, MAIT cells frequently express memory T cell markers and NK cell receptors, but differ from iNKT cells by their tropism for intestinal rather than liver tissues.

NATuRe RevIewS | Immunology 2010 Macmillan Publishers Limited. All rights reserved

effector molecules, such as perforin and granzymes22,34. Moreover, they contribute to pathogen clearance directly through the production of bacteriostatic or lytic molecules, such as granulysin and defensins34,35, and indirectly through the induction of antibacterial functions of other immune effector cells and epithelial cells36. T cells can produce immunomodulatory cytokines that are involved in protective immunity against viruses and intracellular pathogens (tumour necrosis factor (TNF) and IFN), extracellular bacteria and fungi (Il-17), and extracellular parasites (Il-4, Il-5 and Il-13). These cytokine responses also underlie the beneficial or deleterious role of T cells during endogenous stressinduced immune processes, such as tumour-induced inflammation (through production of IFN, Il-6 and granulocytemacrophage colony-stimulating factor (GM-CSF)), autoimmunity (through production of IFN and Il-17), and allergy and asthma (through production of Il-4 and Il-13). Finally, T cells can downmodulate innate and adaptive immune effector cells through the production of immunosuppressive cytokines (transforming growth factor- (TGF) and Il-10), and promote tissue healing and epithelial cell regeneration through the production of epithelial cell growth factors (keratinocyte growth factor 1 (KGF1; also known as FGF7) and KGF2 (also known as FGF10)) and survival factors (eGF1; also known as fibropellin 1) (for recent reviews, see REFs 37,38). T cell programming and plasticity None of the features described in the previous section is unique to T cells, as they are shared with innate immune cells (for example, functions in antibacterial defence and tissue repair), T cells (for example, cytokine responses) and other innate-like T cells (for example, rapid activation kinetics and cell stress recognition). However, the functional specialization of T cell subsets bestows them with a unique ability to carry out a restricted set of tasks with spatial and temporal features that are unmatched by other immune effectors. Functional specialization. As a population, T cells can carry out many diverse functions, but individual subsets within the population have more restricted effector properties, depending on their expressed TCRs, their tissue location and their activation status (TABLE 1). For example, both mouse v5v1+ intraepidermal T cells and v7+ intestinal epithelial lymphocytes (Iels) show enhanced cytoprotective, immunomodulatory and antibacterial functions following epithelial cell injury and/or tumorigenesis, and this is associated with the production of epithelial cell trophic factors (such as KGFs, eGFs and insulin-like growth factor 1 (IGF1)), inflammatory cytokines (such as Il-2 and IFN) and enhanced cytotoxic activity 37. By contrast, mouse v6v1+ T cells mainly produce Il-17 during pulmonary inflammation39, mouse v1v6.3+ T cells produce Il-4 and IFN in the liver 40, and mouse v4+ T cells produce IFN or Il-17 depending on the model studied4143. There seems to be a similar functional specialization of human T cells: human v2+ T cells generally have high cytotoxic activity and produce high levels of IFN and TNF, whereas human v1+ T cells have lower cytotoxic potential and produce a broader set of cytokines, including Il-4 and Il-17 (REFs 44,45). There are similarities and differences in the functional specialization of effector T cells and T cells (BOX 2). Similar to cytotoxic CD8+ T cells, IFN production by T cells is regulated by the transcription factors T-bet and eomesodermin46, similar to TH2 cells and type 2 CD8+ T cells, Il-4 production by T cells correlates with GATA-binding protein 3 (GATA3) expression47 and, similar to TH17 cells, Il-17 production by T cells is controlled by retinoic acid receptor-related orphan receptor-t (RoRt)45,48. Furthermore, similar to classical MHC-restricted T cells, functional polarization in T cells is associated with the expression of distinct chemokine receptors, such as CC-chemokine receptor 5 (CCR5) expression by TH1-like T cells49 and CCR6 for Il-17-producing T cells45,50. However, there are some important differences between the functional specialization of conventional T cells and T cells: the functional specialization of T cells often correlates with the expression of particular TCR variable (v) genes38, the acquisition of regulatory functions by T cells may not require the transcription factor forkhead box P3 (FoXP3) (although human FoXP3+ T cells could be induced in vitro51) and the production of cytokines such as Il-5 and Il-13 by T cells is induced by Il-4 but these cytokines are produced by human T cells in response to Il-2 (REF. 52). Developmental programming. The functional specialization of T cells results from both developmental programming and plasticity in the periphery. we use the term programming to refer to the coordinated acquisition of a restricted TCR repertoire, tissue-homing capabilities and effector functions during intrathymic development that is, before the first encounter with an eliciting agent in the periphery. Plasticity refers to the induction within a given T cell subset in the periphery of specific functions from a larger set of potential activities, depending on its activation context. Developmental programming accounts for the homogeneous TCR repertoire, restricted tissue location and distinct functional properties of mouse T cell subsets expressing invariant TCRs (FIG. 2). Programmed rearrangements of distinct sets of TCR v, diversity (D) and joining (j) segments at different time points of fetal thymus development and a lack of terminal deoxynucleotidyltransferase (an enzyme required for TCR junctional diversification) in fetal T cell precursors favour the production of TCRs with the appropriate canonical junctional sequences and underlie the generation of distinct temporal waves of thymocytes expressing different invariant TCRs during fetal development 53. Selective TCR engagements and their temporal and cellular context during intrathymic development probably determine the set of chemokine receptors expressed and the functional properties of a given T cell subset. For example, engagement of the invariant mouse v5v1 TCR on developing thymocytes by thymic epithelial cells triggers
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Pathogen-associated molecular pattern

(PAMP). Conserved motifs recognized by PRRs that are broadly expressed by various classes of microorganisms but absent from mammals. Examples include lipoteichoic acid (in Gram-positive bacteria), lipoarabinomannan (in mycobacteria), dextran (in fungi), lipopolysaccharide (in Gram-negative bacteria), double-stranded RNA (in viruses) and CpG DNA (in bacteria).

Danger-associated molecular pattern

(DAMP). A conserved mammalian motif, recognized by PRRs, that is broadly upregulated in response to cellular stress. Examples include heat shock proteins, high motility group box 1 protein (HMGB1), DNA-bending proteins and uric acid.

Natural killer receptors

(NKRs). Receptors initially identified on NK cells and later shown to be expressed by some memory T cells as well. NKRs are either related to immunoglobulins (such as killer immunoglobulin-like receptors (KIRs) or to C-type lectins (such as NKRP1 or CD94NKG2). some NKRs (such as the KIRS gene products) deliver activating signals whereas others (such as the MHC class I-specific KIRLl gene products) deliver inhibitory signals.

Natural killer group 2, member D

(NKG2D). An activating lectin-like receptor expressed by most NK cells, CD8+ T cells and T cells. NKG2D is specific for different MHC class I-related ligands that may be upregulated on activated, transformed or virus-infected cells, such as members of the retinoic acid early transcript 1 (RAE1) and cytomegalovirus UL16-binding protein (ULBP) families in rodents and humans, or the MHC class polypeptiderelated sequence A (MICA) and MICB in humans.

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Table 1 | Functional roles of mouse T cell subsets

T cell subset


ND Lymphoid tissue

Effector functions (programmed in the thymus or inducible in the periphery)

Programmed: TNF and IFN Inducible: TH2-type cytokines and IL-17

Role in disease or injury


Resolves lung inflammation Inhibits virus-induced myocarditis Promotes non-specific AHR Inhibits TReg cell development Promotes CGD

78 135 136,137 96 65 72,138 73 40 81 135 139 140 * 71,72 36 43 73 37,110 21 141 116 115 142 39 24 106,108 103 105,107

V5 V6.3 and V6.4 V4 ND

Thymus and spleen Thymus, spleen and liver Lymphoid tissue and lung

Programmed: cytokines are unknown but IL-4 and IL-13 are not produced Programmed: IFN, IL-4, IL-13 and cytotoxicity Programmed: IL-17 Inducible: TNF, IFN and cytotoxicity

Promotes AHR Promotes IgE responses iNKT cell-like properties Kills macrophages in vitro Promotes viral myocarditis and kills virus-infected myocytes Promotes virus-induced lung inflammation Promotes virus-induced encephalitis Inhibits subcutaneous melanoma Inhibits AHR Promotes innate bacterial clearance

Selected V4 V5 V5 V1 invariant

Lymph node Spleen Epidermis

Inducible: IL-17 Programmed: IL-22, IFN, TNF, KGF1, IGF1, CCL5, defensins, MIP1, XCL1 and cytotoxicity ND Programmed: IL-17, IL-22, IFN, TGF and cytotoxicity

Exacerbates CIA Promotes tissue repair and wound healing Protects against skin carcinogenesis Suppresses GVHD Tissue remodelling (lactating mammary gland)? Tissue remodelling (placenta)? Inhibits nephritis Prevents lung fibrosis Promotes innate bacterial clearance

Inducible: IFN-dependent development Suppresses IgE responses

V4 and others V6 V1 invariant

Mammary gland Tongue, uterus, placenta, testes, lung and kidney


V4 and others

Intestinal mucosa

Programmed: TNF, IFN, KGF1 and cytotoxicity

Protects intestinal barrier function Promotes epithelial cell turnover Prevents colitis

AHR, airway hyperresponsiveness; CCL, CC-chemokine ligand; CIA, collagen-induced arthritis; CGD, chronic granulomatous disease; GVHD, graft-versus-host disease; IGF1, insulin-like growth factor 1; IL, interleukin; IFN, interferon-; iNKT, invariant natural killer T; KGF1, keratinocyte growth factor 1; MIP1, macrophage inflammatory protein 1; ND, not determined; TGF, transforming growth factor-; TH, T helper; TNF, tumour necrosis factor; TReg, regulatory T; XCL1, XC-chemokine ligand 1. *Z. Yin, personal communication.

NOD-like receptors
(NLRs). A family of cytoplasmic PRRs that trigger immune responses against microbial threats. For example, NLRP3 senses microbial ligands, endogenous danger signals and certain crystalline substances, and it initiates the assembly of the NLRP3 inflammasome. 22 human and 34 mouse NLR genes have been identified.

the expression of skin homing receptors and TH1-like effector cell functions, allowing early seeding of the epidermis by this particular T cell subset54,55, which is usually referred to as the dendritic epidermal T cell (DeTC) subset. Full maturation of DeTCs involves intrathymic and peripheral interactions with selection and upkeep of intraepithelial T cells 1 (SKINT1), an immunoglobulin superfamily member that is expressed by thymic epithelial cells and keratinocytes56. By contrast, the ability to home to the liver or spleen, to upregulate the co-receptor CD4 and to produce Il-4, Il-13 or IFN is coordinately acquired by mouse thymocytes expressing canonical v1v6.3 TCRs. Similar to iNKT cells, functional programming of v1v6.3 T cells is controlled by the transcription factor promyelocytic leukaemia zinc-finger (PlZF; also known

as ZBTB16)57,58. In vitro TCR crosslinking experiments58 and analysis of mice with genetically altered TCR signalling 47,57,5961 indicate a role for TCR engagement in PlZF upregulation. Moreover, developmental programming of v1v6.3+ T cells involves the engagement of signalling lymphocytic activation molecule (SlAM) family receptors by thymic haematopoietic cells and subsequent SlAMassociated protein (SAP) signalling in the developing T cells, similarly to developing iNKT cells57. Finally, recent studies suggest that ligation of TCR and/or CD27 on certain thymocytes leads to the acquisition of innate TH1 cell-like properties, whereas failure to establish such interactions leads to the generation of thymocytes that are prone to produce Il-17, owing to upregulation (or sustained expression) of RoRt62,63. Although these studies
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Box 2 | Functional subsets of T cells
CD4+ T helper (TH) and CD8+ cytotoxic (TC) cells can be subdivided into functional subsets or lineages, with distinct and heritable functional profiles (reviewed in REFs 132134). TH1 and TC1 cells contribute to inflammatory responses against intracellular pathogens and tumours, and they mainly produce interferon (IFN), which is under the control of the transcriptional regulator Tbet (and eomesodermin in the case of TC1 cells), induced by signalling through the interleukin12 receptor (IL12R). TH2 and TC2 cells contribute to immune defence against extracellular parasites and provide help for IgG1 and IgE class switching. They produce IL4, IL5 and IL13 under the control of the transcriptional regulator GATAbinding protein 3 (GATA3), induced by signalling through IL25R. TH17 and TC17 cells contribute to immune defence against fungi and extracellular bacteria, notably through neutrophil recruitment and activation. They produce IL17A, IL17F, IL21 and IL22 under the control of the transcriptional regulator retinoic acid receptorrelated orphan receptort (RORt), induced by signalling through IL6R and IL21R. Additional functional subsets have been described, which nevertheless might not fulfill all the criteria of a bona fide functional lineage, owing to their heterogeneity or functional plasticity. This is the case for regulatory T cells which downregulate systemic T cell responses and provide help for IgA class switching through the production of transforming growth factor (under the control of the transcriptional regulator forkhead box P3) and follicular T helper cells, which have unique B cell follicle homing features and potent antibody production helper activity.

do not rule out the possibility that TCR interactions with as yet unidentified ligands contribute to TH17-like T cell programming, they suggest that the marked TH17like polarization of the invariant v6v1+ cell subset could result from lack of intrathymic engagement of its TCR during fetal development48. Irrespective of this issue, it has recently been reported that additional signals (such as TGF) in the thymus or after thymus exit have a key role in the commitment of unselected thymocytes to become cells with the ability to produce Il-17 (REF. 64). Functional plasticity. T cells have two kinds of functional plasticity, which we term acquired plasticity and innate plasticity. Acquired plasticity refers to the longlasting ability of a given T cell to exert different sets of co-regulated effector properties in response to TCR signalling and particular environmental cues. This process, shown by the differentiation of naive T cells into TH1 or TH2 cells following priming by viruses or extracellular parasites, respectively, allows the generation of memory T cells with functional attributes that are best suited for the rapid elimination of the eliciting agent during recall infections. By contrast, innate plasticity refers to the context-dependent activation of a particular effector function without long-term functional imprinting. As outlined below, both acquired and innate plasticity contribute to T cell functional specialization. In contrast to the programmed Il-17 production by mouse v6v1+ T cells, v4+ T cells in the lymphoid tissues have no inherent developmental bias towards Il-17 production. However, they acquire such polarization over time in a model of collagen-induced arthritis, accompanied by antigen-driven TCR selection43. Such acquired plasticity might also explain the strong Il-17 response of mouse v1+ cells in chronic granulomatous disease65, as this subset produces TH1- and TH2-type cytokines in other settings. The dichotomy of mouse v1v6.3+ T cells, which include both TH0-like CD4+NK1.1 and TH1-like

Chronic granulomatous disease

(CGD). A human primary immunodeficiency syndrome associated with hyperinflammation and increased susceptibility to bacterial and fungal infections.

Allergic airway hyperresponsiveness

(Allergic AHR; also known as bronchial hyperresponsiveness). A state characterized by easily triggered bronchospasm (contraction of the small airways). AHR is a hallmark of asthma, and it occurs frequently in individuals with chronic obstructive pulmonary disease. It can be induced in mice by allergen sensitization and challenge or by airway exposure to environmental triggers such as ozone. Bronchial challenge with nonspecific agents such as methacholine or histamine is used as a test for AHR.

CD4NK1.1+ populations47, might also reflect their ability to differentiate into different effector types, depending on the context of peripheral activation, a hypothesis that is consistent with the observed enrichment of CD4 NK1.1+v1v6.3+ cells in peripheral hepatosplenic locations40,47,59. The preferential TH1 cell-like polarization of human v9v2+ T cells, characterized by potent TNF and IFN production and cytotoxic responses17,44, is probably acquired during their postnatal peripheral expansion by environmental antigens32. Nevertheless, this subset can still be polarized in vitro into cells with features associated with TH2 cells, TH17 cells, follicular T helper cells or regulatory T cells, depending on the cytokines provided together with the TCR stimuli51,52,66,67. The physiopathological relevance of this acquired plasticity is supported by the observation of reciprocal alterations of TH1 cell-like and TH2 cell-like functions of T cell subsets in patients with HIv infection68, and the correlation between a deviation of ex vivo human v9v2+ T cell responses to a TH2 cell-type and impaired control of mycobacterial infections69. with respect to innate plasticity, the differential induction of particular effector functions may depend on the class of innate receptor that is engaged, the nature of the inflammatory stimuli and the strength of the TCR signal. For example, NKG2D signalling triggers cytotoxic functions of human v9v2+ T cells, thereby influencing lysis or survival of the target cell, but it has more limited effects on cytokine responses70. Il-12 or type I IFNs released by stimulated myelomonocytic cells in response to TlR3 and TlR4 engagement trigger almost exclusive IFN production by human v9v2+ T cells31. Similarly, T cell-derived Il-21 transiently upregulates granzyme B production by human v9v2+ T cells, but only has a limited effect on their cytokine responses67. The DC-mediated peripheral induction of mouse v4+ T cells that suppress allergic airway hyperresponsiveness (AHR) is cytokine dependent, transient, antigen independent and not associated with peripheral TCR selection71,72, and it therefore seems to be based on the innate plasticity of these T cells. Innate plasticity might similarly account for the populations of T cells in the spleen that positively or negatively regulate Ige responses73. v1+ T cells are present in the spleens of normal mice and promote primary Ige responses to intraperitoneal injection of ovalbumin (ovA) in alum, whereas splenic v4+ T cells that suppress an Ige response are induced by repeated airway challenge with ovA, which at the same time leads to loss of the Ige-promoting functions of the v1+ T cells. These examples show the limitations to functional plasticity: although each subset, influenced by external stimuli, might change its function considerably, there seems to be no overlap in functional effects between subsets.

Cellular interplay in health and disease Interplay with innate cells. The rapid release by resident T cells of potent chemoattractants for neutrophils and macrophages in response to tissue stress contributes to the early recruitment of several innate immune effectors (FIG. 3a). In this respect, T cells were recently shown to be the primary sources of the neutrophil-attracting

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Programmed TCR rearrangements TEC V5 TCR V1 SKINT1 Thymic cell of haematopoietic origin V1 V6.3 SLAMF Fetal precursor V6 V1 TGF SAP1 PLZF+ IL-23R CCR6 AHR RORt+ NK1.1 T-bet+ EOMES+ CD4(+/) Liver and spleen Intrathymic functional programming CD122 CCR10 T-bet+ EOMES+ IL-22, IFN and TNF V1V6.3 TCR Peripheral homing and activation Epidermis V5V1 TCR

PLZF+ T-bet+ IL-4, IL-13 and IFN Uterine, vaginal, tongue and lung epithelia V6V1 TCR

RORt+ IL-17, IL-22, IFN and TGF


Figure 2 | Functional programming of invariant or invariant-like T cell subsets. Through programmed rearrangements, fetal precursors generate successive waves of T cells expressing V5V1, V1V6.3 or V6V1 T cell receptors (TCRs) with invariant or highly related junctional sequences. SKINT1 (selection and upkeep of intraepithelial T cells 1)-dependent interactions between invariant mouse V5V1+ T cells and thymic epithelial cellsReviewsinduce Nature (TECs) | Immunology early commitment to a T helper 1 (TH1) cell-like phenotype and the acquisition of receptors that promote homing to the skin (CC-chemokine receptor 10 (CCR10)). Exit from the thymus depends on sphingosine 1-phosphate receptor 1 (S1PR1). V5V1+ thymocytes then migrate to the epidermis where they acquire their typical dendritic morphology. SLAM-associated protein 1 (SAP1)-dependent interactions between V1V6.3+ T cells and thymic cells of haematopoietic origin, presumably in conjunction with TCR engagement, upregulate expression of the transcription factor promyelocytic leukaemia zinc-finger (PLZF) and subsequent upregulation of CD4 and natural killer 1.1 (NK1.1) and production of interleukin-4 (IL-4), IL-13 and interferon- (IFN), which are under the control of the transcription factors PLZF and T-bet. Lack of TCR engagement by thymocytes expressing invariant V6V1 TCRs presumably leads to a transforming growth factor- (TGF)-dependent default pathway associated with acquisition of TH17 cell-like properties, under the control of the transcription factor retinoic acid receptor-related orphan receptor-t (RORt), and the ability to home to uterine, vaginal, tongue and lung epithelia. AHR, aryl hydrocarbon receptor; EOMES, eomesodermin; R, receptor; SLAMF, signalling lymphocytic activation molecule F; TNF, tumour necrosis factor.

Il-17 in mouse models of infection24, hypersensitivity 39 and autoimmunity 43. As recently reported, the high level of Il-17 production by T cells in particular locations, such as the peritoneum, seems to depend largely on prior induction or expansion of Il-17-producing T cell subsets in response to commensal bacteria74. Human T cells also produce Il-17 and, in patients with active pulmonary tuberculosis, they can constitute most of the Il-17+ cells75. Il-17 production is restricted to certain types of either innate (v6v1+) or acquired (v4+) cell subsets in mice, which are activated at early or late stages of the immune response, respectively. Innate and acquired Il-17+ T cells also differ in their functional potential only innate Il-17+ T cells retain the ability to produce IFN and are inducible by cytokines alone, whereas acquired Il-17+ T cells are induced by TCR signalling together with TH17 cellpolarizing cytokines and in their involvement in the
NATuRe RevIewS | Immunology

various disease processes48. For example, early Il-17 production by mouse v6v1+ T cells during infection and sepsis is induced by Il-23 seemingly without concomitant TCR engagement, whereas TCR signals might be required for Il-17 production by T cells in sterile inflammation48. The observation of impaired neutrophilic responses and bacterial clearance in TCR -chain-deficient mice indicates a crucial and beneficial role for early Il-17 production by T cells in these processes76. Consistent with this, early Il-17 production by innate mouse v6v1+ T cells inhibits lung fibrosis in a model of bacteria-induced hypersensitivity pneumonitis39 and bleomycin-induced lung injury 77. However, Il-17-producing T cells can also be pathogenic in several immune-mediated diseases. In particular, depletion of mouse v4+ T cells that mediate an antigen-driven Il-17 response during collagen-induced arthritis reduces disease incidence and severity 43.
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a Early: innate boost
Epithelium Mature DC Stress detection and T cell activation Proliferation and polarization T cell activation T cell
Proliferation and polarization

b Intermediate: adaptive boost

Immature DC

c Late: downmodulation of immune responses

and tissue repair Polarized T cells Maturation

Trophic factors

Tissue repair

Programmed T cells IL-17 CCL2


Killing and suppression



Innate cell recruitment and activation

Programmed or polarized T cells Monocyte or macrophage B cell activation

Activated T cell macrophage

Neutrophil Monocyte or macrophage

Figure 3 | Cellular interplay involving T cells. a | Early boosting of innate responses. Following sensing of stress Nature Reviews | Immunology signals on epithelial cells or dendritic cells (DCs), tissue-resident T cells with programmed effector functions promote the recruitment and activation of innate cells (such as neutrophils through interleukin-17 (IL-17) production, or monocytes and macrophages through CC-chemokine ligand 2 (CCL2) production). b | Intermediate boosting of adaptive immune responses. Crosstalk between T cells and DCs leads on the one hand to proliferation and functional polarization of T cells and on the other hand to maturation of immature DCs. Both programmed and polarized T cells modulate functional polarization of T cells together with mature DCs and promote B cell responses and antibody class switching. c | Late downmodulation of immune responses and tissue repair. T cells downmodulate inflammation and immune effectors through cytotoxicity and immunosuppressive cytokines. They also contribute to tissue repair through local release of epithelial cell growth and survival factors and recruitment of innate effector cells.

B cell

Mice defective for indoleamine 2,3-dioxygenase (IDo), an enzyme involved in the catabolism of tryptophan, spontaneously develop a chronic granulomatous disease-like syndrome. These mice develop a strong Il-17 response mediated by acquired v1+ T cells together with enhanced neutrophilic infiltration to the lungs and subsequent acute lung injury, which could be ameliorated by neutralization of Il-17 or T cell depletion65. The activation of T cells in mice following clearance of influenza virus infection suggests a role for T cells in the resolution of the innate inflammatory responses78. These late T cell responses contribute in a non-redundant manner to the downmodulation of infection-induced inflammation, as indicated by the larger and longer-lasting inflammatory lesions in TCR -chain-deficient mice than wild-type mice challenged with intracellular bacteria79. This effect might be explained in part by enhanced macrophage recruitment80 but also by T cell-mediated killing of activated macrophages81, possibly through recognition of conserved ligands that are upregulated during inflammation12 (FIG. 3c). Innate-like v6v1+ T cells seem to be responsible for the initial recruitment of macrophages, whereas the subsequent phase of macrophage lysis depends on acquired v4+ and v1+ T cells78. Interplay with antigen-presenting cells and conventional T cells. DCs are potent inducers of T cell effector functions owing to their ability to express ligands for TCRs and NKRs and to provide co-stimulation signals
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that synergize and sometimes bypass TCR engagement (FIGs 3b, 4). For example, DCs stimulate more TNF and IFN production by phosphoantigen-stimulated human v9v2+ T cells than other types of antigen-presenting cell (APC)29. Moreover, after TlR3 or TlR4 engagement, DCs release Il-12 or type I IFNs that induce IFN production by human v9v2+ T cells in a TCR-independent manner 31. Similarly, in mouse models of arthritis and brain ischaemiareperfusion injury 82,83, DCs activated through ligation of TlR2 or NoD receptors become a potent source of Il-23 that supports Il-17 production by T cells. Finally, in a mouse model of AHR, adoptively transferred CD8+ DCs supported the induction of mouse v4+ T cells that suppress AHR72. In this interplay, direct contact between T cells and splenic CD8+ DCs seems to be essential. In turn, interactions between T cells and DCs induce DC activation and differentiation by several mechanisms (FIG. 3b). For example, IFN produced by phosphoantigen-stimulated human v9v2+ T cells enhances, through an IFN- and Il-12-mediated positive feedback loop, Il-12 production by DCs, which can then promote the development of TH1-type T cells29. Human v9v2+ T cells similarly induce rapid differentiation of monocytes into inflammatory DCs, which can trigger, under the influence of further microbial stimuli, polarized development of T cells expressing IFN or Il-17 (REF. 84). Finally, in a mouse model of uveitis induced by immunization with an autoantigenic peptide, Il-17-producing T cells could directly promote the development of other Il-17-producing T cells85.

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Antigen-stimulated human v9v2+ T cells were recently shown to display several hallmarks of professional APCs, such as upregulation of MHC class I and class II molecules and of the co-stimulatory molecules CD40 and CD83, ability to phagocytose and process antigen, and ability to activate naive T cells8688. Although these features might also apply to some mouse T cells89, so far all of these observations have been made from studies in vitro. It remains to be determined when and where APC functions of T cells might have a role in vivo, and whether the APC function is indeed a unique attribute of T cells compared with other T cell subsets. T cells can also negatively regulate T cell activation and inflammation during infections, tumours and autoimmune processes (FIG. 3c). The inhibitory mechanisms involved are varied and include accelerated pathogen clearance owing to enhanced recruitment of innate cells, direct elimination of activated macrophages, DCs or T cells81,9092 and production of cytokines (such as TGF and Il-10) that suppress T cell-dependent inflammation 91,92. Although these processes might inhibit pathogenic T cell responses in autoimmune situations93,94, they can be deleterious if they target tumour-specific T cells (for example, in human breast and prostate cancers)95 or regulatory T cells (for example, in mouse AHR models)96. Interplay with B cells. The original observation that T cell-deficient mice still developed normal germinal centres and class-switched antibodies suggested that T cells might be able to provide help in these processes instead of T cells97. Consistent with this hypothesis, T cell help for B cells could be induced in a parasitic infection in the absence of other T cells98. Compared with wild-type mice, T cell-deficient mice showed decreased levels of ovA-specific Ige and IgG1 antibodies in the blood after intraperitoneal immunization with ovA, which were restored with administration of Il-4, implicating T cells as a probable source of this crucial cytokine99. By contrast, repeated airway challenge of mice with ovA induced splenic T cells that could suppress the primary Ige response to this antigen100. As mentioned earlier, these opposing Ige regulatory effects are mediated by different T cells: spontaneously developing v1+ T cells including the v1v5+ subset enhance Ige responses, whereas inducible (acquired) v4+ T cells suppress the T cell-dependent antigen-specific Ige responses73. Accordingly in a model of mycobacterial infection, T cell-dependent germinal centre formation and Ige production were linked to CD4+ Il-4-producing T cells and regulated through CD5-mediated inhibition101. In humans, involvement of v9v2+ T cells in B cell help is supported by their ability to produce B cell co-stimulatory molecules (such as CD40 ligand, CD70 and inducible T cell co-stimulator (ICoS)) and their presence in gastrointestinal lymphoid tissues, in clusters within germinal centres of B cell follicles102. Consistent with this, Il-21 induces in vitro acquisition of follicular T helper cell features by human v9v2+ T cells, such as a lymphoid homing phenotype and high-level expression of the follicular B cell-attracting chemokine CXC-chemokine ligand 13 (CXCl13)52.
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Figure 4 | T celldendritic cell interactions|in a normal Nature Reviews Immunology mouse lung. A V4+ T cell (red), which might have arrived in the lung through a nearby blood vessel (green), is observed interacting with an MHC class II-expressing pulmonary dendritic cell (DC; blue). At any one moment, ~50% of the T cells in the normal adult C57BL/6 mouse lung can be seen making such contacts, suggesting a continuous monitoring of the more frequent DCs by relatively few T cells. The inset shows high-level T cell receptor (TCR) staining at the interface between the T cell and DC, which might indicate engagement of the TCRs during this cellular interaction. Image from J. M. Wands (National Jewish Health, Denver, Colorado, USA).

Interplay with non-immune cells. The distinct tissue tropism of T cells and close contacts with epithelial and endothelial cells implies involvement in crosstalk with non-immune cells (FIGs 3a,c). Accordingly, decreased turnover of intestinal epithelial cells in TCR -chaindeficient mice suggested that T cells can promote epithelial cell homeostasis103. In two mouse models of villus atrophy and hypertrophy, KGF1 expression was highest in the intestinal crypts and restricted to Iels104. In addition, colitis induced in wild-type mice by administration of dextran sodium sulphate or haptens was associated with infiltration of KGF1-producing Iels in the inflamed mucosa and, if induced in TCR-deficient mice, was associated with delayed epithelial cell recovery 105107. Iels express some of the junctional molecules that hold epithelial cells together, including e-cadherin (also known as cadherin 1) and occludin, the expression of which is increased by TCR stimulation108. This feature might be important for T cells to sustain epithelial barrier function109. In the skin, intraepidermal mouse v5v1+ DeTCs, which recognize stressed keratinocytes, contribute to epithelial cell homeostasis through the production of various different factors, including KGFs and IGF1 (REF. 37). DeTCs become activated in skin wounds through TCR stimulation110, and they release KGFs that trigger hyaluronan production by neighbouring keratinocytes111 and subsequent recruitment of macrophages that promote wound repair. Similar to their mouse counterparts, human skin-infiltrating v1+ T cells isolated from acute wounds produce IGF1 and contribute to accelerated wound closure in in vitro models112. Mouse T cells also contribute to epithelial cell repair after corneal epithelial cell abrasion113 and after lung exposure to ozone or bleomycin114. T cells from injured lungs rapidly produce Il-17, which promotes the recruitment of neutrophils76,
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which in turn promote accelerated renewal of the airway epithelium77. Finally, transient T cell expansions in the placenta115 and lactating mammary glands116 suggest their involvement in the remodelling of these rapidly changing epithelial cell tissues. relapsing after antibody treatment. Preliminary findings suggest a higher complete clinical response rate than expected from groups treated with rituximab alone in previous studies125. If confirmed, such results would warrant a more formal assessment of the risk/benefit ratio of such a combination approach in larger patient cohorts.

Antibody-dependent cell cytotoxicity

(ADCC). A cytotoxic mechanism mediated by engagement of low-affinity receptors for the constant fragment of IgG (FcRIII; also known as CD16) by antibody-coated target cells.

Clinical implications The studies in mice have provided important clues to the physiological roles of T cells (TABLE 1), but owing to the differences between mouse and human T cell subsets examined so far, these studies have not generally predicted the behaviour of human T cells. Nevertheless, comparison of functionally analogous subsets in both species can bring insight into human T cell immunobiology. For example, modalities of wound healing by cutaneous human v1+ T cells can be indirectly addressed through analysis of mouse v5v1+ DeTCs, as both subsets can produce epithelial cell growth factors in response to tissue injury 110113. Similarly, mouse liver v1v6.3+ T cells yield a T cell lymphoproliferative disease in mutant mice with altered TCR signalling 60 that shows similarities with human hepatosplenic T cell lymphomas117. Therefore, analysis of mouse v1v6.3+ T cell functions might provide insights into the aetiology of this rare human neoplastic disease. Immunotherapies targeting human v9v2+ T cells have been recently developed, taking advantage of the high frequency and broad antitumour and antimicrobial properties of this subset 118. Available clinical-grade compounds act either directly to activate v9v2+ T cells (such as the synthetic phosphoantigens bromohydrin pyrophosphate (Phosphostim; Innate Pharma) and cHDMAPP (Picostim; Innate Pharma) or induce intracellular accumulation of human v9v2+ T cell agonists (such as the aminobisphosphonates pamidronate (Aredia; Novartis) and zoledronate (Zometa/Zomera/Aclasta/ Reclast; Novartis))118. Both types of molecule have been tested in primates to assess the in vivo consequence of v9v2+ T cell activation in health and disease119 and were shown to induce accelerated pathogen clearance and repair of inflamed tissues after Yersinia pestis infection120. Based on these preclinal data, Phase I and II clinical trials were recently carried out in patients with cancers and chronic viral infections121,122. Co-administration of human v9v2+ T cell agonists and Il-2 in these patients induced efficient in vivo activation and expansion of T cells with limited adverse events. Moreover, in vivo v9v2+ T cell amplification after treatment correlated with disease stabilization or partial tumour regression in patients with multiple myeloma or hormone-resistant metastatic prostate carcinomas121,122. In a recent Phase II clinical trial, phosphoantigen treatment also induced a rapid decrease in hepatitis C viral loads in 50% of chronically infected patients, presumably through promotion of T cell-mediated IFN responses123. Finally, the ability of human v9v2+ T cells to kill tumour cells through antibody-dependent cell cytotoxicity124 was exploited in a clinical trial combining a B cell lymphoma-specific monoclonal antibody (rituximab (Rituxan/Mabthera; Genentech/Roche/Biogen Idec)) and phosphoantigens plus Il-2 in patients with follicular B cell lymphoma

Concluding remarks Despite recent progress in the understanding of stress sensing by T cells, the structural features and recognition modalities of most TCR ligands remain unknown, and the question of whether T cells recognize structurally related molecules remains open. Addressing this question should provide important clues about the coevolution of TCRs and their ligands, and the phylogenetic pressure exerted on particular T cell subsets with seemingly mandatory functions. Moreover, characterization of antigens recognized by TCRs should improve our understanding of the regulation of T cells by inflammatory and stress signals and the mechanisms controlling the distinct temporal engagement of T cell subsets in the course of disease. Furthermore, the fine modalities of functional differentiation of developing T cells and activation of their effector functions also remain elusive. Detailed understanding of these processes will require elucidation of at least four key issues: first, how transcription factors associated with either TH1 cell-like functional programmes (that is, T-bet) or TH0 cell-like functional programmes (that is, PlZF) are differentially induced in positively selected thymocytes. Second, whether TCR signals are required for intrathymic selection, functional programming or peripheral activation of innate TH17 cell-like T cell subsets, such as the invariant mouse v6v1+ subset. Third, if TCR signals are not required, what might be the mechanisms underlying the generation of invariant mouse v6v1 TCRs with junctional sequences that are identical to those of positively selected invariant mouse v5v1 TCRs and, finally, what non-TCR signals are involved in the early or late functional commitment of innate and acquired T cell subsets. From a clinical point of view, one notable drawback of current immunotherapies targeting human v9v2+ T cells is the rapid exhaustion of proliferation and effector responses by these cells after repeated treatments with phosphoantigens or aminobisphosphonates118. The underlying mechanisms of this phenomenon remain unknown, but could reflect in vivo stimulation of these cells in a suboptimal cellular context. Detailed characterization of anergic T cells induced by repeated phosphoantigen or aminobisphosphonate treatments and of the factors required for sustained activation and long term survival of T cells will probably be required to solve this key issue. Finally other T cell subsets (v2) are also promising immunotherapeutic targets against infections and tumours, as they generate strong responses against mycobacteria126, herpesviruses127 and solid tumours16. Clearly, characterization of the antigen recognized by these v2 T cells remains a prerequisite for therapeutic exploitation of their broad antimicrobial and antitumour properties.

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We thank H. Sicard (Innate Pharma, Marseilles, France) for helpful suggestions, Z. Yin (Yale School of Medicine, New Haven, Connecticut, USA) for personal communication and J. M. Wands (NJH, Denver, Colorado, USA) for the image used in figure 4.

Competing interests statement.

The authors declare competing financial interests: See Web version for details.

UniProtKB: http://www.uniprot.org CD1c | CD1d | CD95 | dectin 1 | E-cadherin | EGF1 | GM-CSF | granzyme B | IFN | IGF1 | IL-4 | IL-5 | IL-6 | IL-10 | IL-13 | IL-17 | KGF1 | KGF2 | MR1 | occludin | PLZF | SKINT1 | TLR2 | TLR3 | TLR4 | TNF

Marc Bonnevilles homepage: www.crcna.univ-nantes.fr/

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