The TIM (T-cell immunoglobulin domain and mucin domain) family of genes was first discovered in 2001 and received much atten-tion due to its location on mouse chromo-some 11B1.1, a genetic region associated with multiple diseases including asthma, allergy and autoimmunity1. In mice, there are four expressed Tim genes: Havcr1 (hepatitis A virus cellular receptor 1; also known as Timd1; which encodes TIM1), Timd2 (which encodes TIM2), Havcr2 (also known as Timd3; which encodes TIM3) and Timd4 (which encodes TIM4), and four predicted Tim genes, Tim5, Tim6, Tim7 and Tim8 (also known as Dppa1). Of these, three are conserved in humans: HAVCR1 (which encodes TIM1), HAVCR2 (which encodes TIM3) and TIMD4 (which encodes TIM4). As indicated by their names, TIM molecules were initially thought to be specifically expressed on the surface of T cells and to function in directly regulating T-cell responses. Indeed, TIM1, TIM2 and TIM3 were all found to be expressed by T cells, and early studies suggested an interesting paradigm for the TIM proteins in T helper (TH)-cell regulation; TIM1 was thought to regulate interleukin-4 (IL-4)-secreting TH2 cells and TIM3 was thought to regulate interferon-γ (IFNγ)-secreting TH1 cells.

However, in the past few years, investigation of TIM2 and TIM4, and further investigation of TIM1 and TIM3 has revealed that the TIM proteins are expressed by other immune-cell types,

notably antigen-presenting cells (APCs), and have more complex roles in immune regulation. Identification of several TIM-protein ligands has further increased our knowledge of the function of these proteins in the immune system (FIG. 1). In addition, the elucidation of the crystal structures of all four TIM molecules has revealed a unique structural motif that is shared among the TIM proteins.

Here, we highlight the emerging role of TIM-mediated regulation of multiple TH-cell subsets, their function in activating APCs to promote inflammation and T-cell priming, and how the recent elucidation of the crystal structures of the TIM proteins has revealed unique binding structures and led to research suggesting a role for the TIM proteins in the clearance of apoptotic cells.

Regulation of T‑cell responses by TIMsTIM1: beyond TH2 cells.TIM1 is expressed by all activated CD4+ T cells and, after differentiation, its expression remains high on TH2 cells but is reduced on TH1 and TH17 cells2–4. Early studies showed that T-cell activation in the presence of a TIM1-specific agonist antibody promoted IL-4 production by TH2 cells, but had no effect on IFNγ production by TH1 cells2. Furthermore, administration of a TIM1-specific agonist antibody substantially increased the production of IL-4, IL-10 and IFNγ by CD4+ T cells, prevented the development of tolerance to intranasally

administered antigen and increased airway inflammation2. These data gave rise to the hypothesis that TIM1 has an important role in the regulation of TH2-cell responses. Indeed, antibodies against different epitopes of TIM1 have been found to either enhance or decrease airway inflammation by altering TH2-cell responses in mouse models of asthma5. Studies of TIM1 signal-ling further substantiated the role of TIM1 in promoting TH2-cell responses: cells transfected with the gene encoding TIM1 showed increased transcription of IL-4 and spontaneous activation of nuclear factor of activated T cells (NFAT) and activator protein 1 (AP1) elements6. Collectively, these studies supported an important role for TIM1 in T-cell activation and in the promotion of TH2-cell responses.

Despite in vitro data suggesting a role for TIM1 in promoting TH2-cell responses, treatment of mice with the TIM1-specific agonist antibody in vivo was found to increase IFNγ production by CD4+ T cells following immunization2. In addition, the TIM1-specific agonist antibody enhanced the expansion and survival of alloreactive TH1 and TH17 cells and prevented the induction of tolerance by CD40 ligand (CD40L)-specific therapy in mice that had received pancreatic islet transplants7. Interestingly, this same study showed that TIM1-specific agonist antibody decreased the suppressive capacity of natural regula-tory T (TReg) cells, in line with a reduction in their expression of FOXP3 (forkhead box P3), GITR (glucocorticoid-induced tumour-necrosis factor (TNF)-receptor-related protein), CTLA4 (cytotoxic T-lymphocyte antigen 4) and IL-10. In addition, the de novo generation of FOXP3+ TReg cells from FOXP3– precursors was inhibited7. Using two different TIM1-specific antibodies — one that binds TIM1 with high affinity and has agonistic properties, and the other that binds TIM1 with lower affinity and has blocking properties — we have observed opposing effects on T-cell activation and tolerance in vivo. Although the basis for the dif-ferential effects of these two antibodies is not known, it is possible that they activate different signalling pathways downstream

New roles for TIM family members in immune regulationVijay K. Kuchroo, Valerie Dardalhon, Sheng Xiao and Ana C. Anderson

Abstract | Members of the TIM (T-cell immunoglobulin domain and mucin domain) protein family are emerging as important regulators of immune responses. As their names imply, the TIM proteins were originally thought to be T-cell-specific molecules that served mainly to regulate T-helper-cell responses. However, the recent discovery that antigen-presenting cells also express TIM molecules and the identification of new TIM-protein ligands has expanded the known roles of the TIM proteins in immune regulation.

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Progress

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Nature Reviews | Immunology

TIM4 TIM1 TIM1 TIM2 TIM2

TIM3

Apoptotic body or exosome

RGDmotif

H-ferritinSEMA4A

Unknown ligand

IgV domain

O-linked glycosylation

N-linked glycosylation

Galectin-9Mucindomain

PtdSer

Plasma membrane

a b c

of TIM1. The high-affinity TIM1-specific agonist antibody increases antigen-specific T-cell proliferation and production of IFNγ and IL-17 but not of IL-4 or IL-10. Furthermore, administration of the high-affinity TIM1-specific agonist antibody during the induction of autoimmunity in the central nervous system dramatically enhances pathogenic TH1- and TH17-cell responses and increases the incidence and severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis8. By contrast, the low-affinity TIM1-specific blocking antibody increases TH2-cell responses and inhibits antigen-specific T-cell proliferation, the production of TH1- and TH17-type cytokines and the development of EAE8. Similarly, the blocking antibody prolongs the survival of fully MHC-mismatched vascularized mouse cardiac allografts by inhibiting alloreactive TH1-cell responses and preserving TH2-cell responses9. Interestingly, graft survival was abrogated by the depletion of natural TReg cells in this model. Collectively, these data suggest that in addition to regulating TH2-cell responses, TIM1 also regulates TH1-, TH17- and TReg-cell responses. The question that remains is how TIM1 regulates all of these different T-cell responses. It is pos-sible that TIM1 achieves its multiple effects through interactions with different ligands expressed by different cell types and/or that TIM1 itself can be expressed by other cells involved in T-cell activation, such as APCs.

while analysing the molecular mecha-nisms by which TIM1 can differentially regulate T-cell responses, we questioned whether TIM1 is part of the T-cell receptor (TCR)–CD3 complex and speculated that if it is, depending on the affinity with which TIM1 binds its ligand, there might be differential effects on TCR–CD3 capping and cytoskeletal reorganization. Although both high- and low-affinity TIM1-specific antibodies enhanced TCR–CD3 capping, only the high-affinity agonist antibody induced cytoskeletal reorganization and T-cell motility, suggesting that crosslinking of TIM1 can alter T-cell function depend-ing on the affinity and/or avidity with which it is engaged8. Therefore, different outcomes for T-cell activation are probable depending on the affinity of the ligand for TIM1. Other investigators have also proposed that TIM1 may form part of the TCR–CD3 complex during T-cell activa-tion and thereby regulate T-cell activation and proliferation by reorganizing signalling molecules10.

TIM2: a negative regulator of TH2-cell responses. TIM2, which is most similar to TIM1, is not expressed by naive T cells but is upregulated preferentially by TH2 cells11. Unlike TIM1, which might affect T cells other than TH2 cells, TIM2 seems to be a specific regulator of TH2-cell responses. Administration of a TIM2–immunoglobulin fusion protein results in the preferential

induction of TH2-cell responses, inhibition of TH1-cell responses and delayed disease progression with reduced disease severity in EAE11. Furthermore, antibodies against semaphorin 4A (SEMA4A), a putative ligand of TIM2 (FIG. 1), also inhibit the development of EAE12, and mice lacking SEMA4A show dysregulated TH-cell differentiation and impaired TH1-cell responses13. Indeed, mice lacking TIM2 exhibit dysregulated TH2-cell responses and exacerbated lung inflammation in a TH2-cell-driven model of airway inflammation14. Biochemical analyses of TIM2 signalling showed that overexpression of TIM2 significantly impaired the induction of NFAT and AP1 (ReF. 15). Collectively, these data are consist-ent with a model in which TIM2 expression by TH2 cells functions to negatively regulate T-cell responses.

TIMs in innate cellsTIM4: bimodal effects on T-cell activation. Unlike the other TIM proteins, TIM4 is only expressed by APCs and not by T cells3,16. Although not expressed by T cells, TIM4 has a role in T-cell activation. TIM4 has been shown to be a ligand for TIM1 and to act as a co-stimulatory molecule that promotes T-cell expansion and survival16. Indeed, interaction with TIM4 specifically leads to TIM1 phosphorylation and promotes T-cell proliferation by enhancing cell division and reducing apoptosis. These effects are due to the fact that TIM4, together with TCR crosslinking, induces the phosphorylation of the signalling molecules LAT (linker for activation of T cells), AKT and ERKs (extracellular-signal-regulated kinases) in T cells16. Interestingly, qualitatively dif-ferent outcomes have been observed after stimulation with different concentrations of TIM4–immunoglobulin fusion protein: high concentrations enhance T-cell proliferation, whereas low concentrations inhibit T-cell proliferation3, suggesting bimodal regulation of T-cell responses by TIM4. In fact, a recent study has shown that TIM4 inhibits the acti-vation of naive but not pre-activated T cells and that this inhibitory effect depends on an unidentified TIM4 ligand, as naive T cells do not express TIM1 (ReF.17). These data suggest that there are at least two ligands for TIM4, one that inhibits T-cell activation and another that promotes it.

TIM3 and its role in innate immunity. TIM3 was first identified as a molecule that is specifically expressed by terminally differentiated TH1 cells18, and it was shown to lead to the death of effector TH1 cells

Figure 1 |mouseTimfamilyproteinsandtheirligands.a|TIM4 (T-cell immunoglobulin domain and mucin domain 4) binds to TIM1 and contributes to T-cell activation and expansion. Both TIM1 and TIM4 can bind to phosphatidylserine (Ptdser) through the Fg-CC′ binding cleft in their N-terminal immunoglobulin variable (IgV) domain and thereby facilitate the clearance of apoptotic cells or bodies. TIM4 also contains an rgD (arginine, glycine, aspartic acid) motif, which is found in many ligands that bind integrins. In addition, TIM1 can interact with itself. b| semaphorin 4A (seMA4A) and H-ferritin bind to TIM2. c| galectin-9 binds to TIM3 through N-linked carbohydrates attached to the IgV domain. An as-yet-unknown ligand is likely to bind to the Fg-CC′ cleft on the opposite side of the TIM3 IgV domain.

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Nature Reviews | Immunology

TNF

Inhibition of TH1-cell responses

DC

TLR

TLR ligand

Galectin-9TIM3

IFNγ

IFNγ

T cell

TH1 cell

T cell, antigen-presenting cell or tissue cell

Apoptotic T cell

Priming phase

Effector phase

Promotion of T-cell responses

on binding to its ligand, galectin-9 (also known as LGALS9)19. Although Tim3 mRNA was also initially detected in mouse CD11b+ cells and cells other than T cells, at that time, no evidence for a protein encoded by the Tim3 gene was found. Recently, we demonstrated that TIM3 is constitutively expressed by mouse CD11c+ dendritic cells (DCs) and not by CD11b+ macrophages20. Similarly, TIM3 is highly expressed by human DCs and at a lower level by human monocytes. The discovery of TIM3 expression by DCs challenged our understanding of the functions of this molecule as it opened new perspectives on the function of TIM proteins in the immune system and revealed a potential role in innate immune responses. Indeed, stimulation of TIM3 in mouse DCs and human monocytes promoted the secretion of pro-inflammatory cytokines (such as TNF). Moreover, responsiveness to Toll-like receptor (TLR) ligands was impaired in the absence of TIM3 signalling, suggest-ing synergy between the TIM3 and TLR signalling pathways.

These findings suggest that TIM3 has opposing roles in innate and adaptive immu-nity. During the initiation of an immune response, TIM3 expressed by DCs probably

promotes inflammation by synergizing with TLRs. Once an effector TH1-cell response is generated, TIM3 is expressed by termi-nally differentiated TH1 cells, which then upregulate galectin-9 expression through the production of IFNγ. Finally, galectin-9 binds TIM3 on the surface of TH1 cells and inhibits the TH1-cell response by triggering cell death19 (FIG. 2).

How can ligation of the same molecule on different cell types mediate such different effects? Studies that compared the signalling pathways induced after TIM3 engagement on T cells and DCs provide a biochemical basis for the different functions of TIM3 in the two cell types. Although ERK phospho-rylation and IκBα (inhibitor of nuclear factor-κBα) degradation were similar fol-lowing TIM3 ligation, the tyrosine phospho-rylation pattern was different in T cells and DCs, suggesting that TIM3 ligation induces distinct signalling events and therefore different functions in the two cell types20.

TIM structures reveal a role in clearance of apoptotic cells. All TIM molecules are type I cell-surface glycoproteins and have a com-mon structure that includes an N-terminal immunoglobulin variable (Igv) domain fol-lowed by a mucin domain, a transmembrane

domain and a cytoplasmic tail (FIG. 1). The mouse TIM1, TIM2, TIM3 and TIM4 Igv domains have recently been crystallized and their structures elucidated21–23. The crys-tal structures reveal the presence of a unique binding cleft (FG-CC′ cleft) not found in the structure of other immunoglobulin super-family members. This cleft is conserved among the TIM family proteins, with the exception of TIM2. The conformation of the CC′ loop in TIM2 is markedly different from that of TIM1, providing a possible structural basis for the different functions of TIM1 and TIM2. Interestingly, the FG-CC′ cleft does not mediate galectin-9 and TIM3 binding, nor the interaction between TIM1 and TIM4. Thus, the presence of the FG-CC′ cleft suggests the existence of additional TIM ligands, some of which could be shared among the TIM proteins.

Indeed, several recent studies have found that the FG-CC′ cleft in TIM1 and TIM4 is a binding site for phosphatidyl-serine and that TIM1 and TIM4, but not TIM2 or TIM3, can bind to phosphatidyl-serine exposed on the surface of apoptotic cells23–25. Indeed, expression of TIM1 or TIM4 in fibroblasts enhances their ability to phagocytose apoptotic cells in vitro and this can be blocked by either TIM1- or TIM4-specific antibodies24,25. In addition, TIM1 and TIM4 might have a role in intercellular signalling through the binding of phosphatidylserine on the surface of exosomes, which are small secreted vesicles that function as intercellular messengers and stimulate immune responses. It should, however, be emphasized that although both mouse and human TIM1 and TIM4 can act as receptors for phosphatidylserine in vitro, a biologically important role for TIM1 and TIM4 in clearing apoptotic cells in vivo has not been shown. with the development of mice deficient in TIM1 or TIM4, it will be possible to address the in vivo role of these proteins in clearing apoptotic cells and their potential involvement in regulating systemic autoimmune diseases that are associated with a defect in the clearance of apoptotic bodies.

TIMs: perspectives on human diseaseHuman TIM3 shares 63% amino-acid identity with mouse TIM3 and is also preferentially expressed by TH1 cells26. In agreement with the negative regula-tory function of mouse TIM3 expressed by TH1 cells, reduction of human TIM3 expression by small interfering RNA or by TIM3-specific blocking antibodies results in increased IFNγ secretion by human

Figure 2 | modelofTim3functionintheimmunesystem.In the steady-state immune system, TIM3 (T-cell immunoglobulin domain and mucin domain 3) is expressed mainly by dendritic cells (DCs). TIM3 signalling in DCs synergizes with that of Toll-like receptors (TLrs) and this leads to the activation of DCs, the production of pro-inflammatory cytokines (such as tumour-necrosis factor (TNF)) and the promotion of T-cell priming. once a T helper 1 (TH1) cell is generated, TIM3 is expressed by terminally differentiated TH1 cells, and expression of the TIM3 ligand, galectin-9, is upregulated through the secretion of interferon-γ (IFNγ). galectin-9 then terminates the TH1-cell response by triggering cell death in TIM3+ TH1 cells.

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CD4+ T cells27,28. Interestingly, T-cell clones isolated from the cerebrospinal fluid of patients with multiple sclerosis express lower levels of TIM3 and secrete higher levels of IFNγ compared with T-cell clones isolated from healthy control subjects27. Moreover, CD4+ T cells from patients with multiple sclerosis show altered kinetics of TIM3 expression and are refractory to the blocking effects of TIM3-specific anti-bodies28. Collectively, these data suggest that the TIM3 pathway is dysregulated in patients with multiple sclerosis and high-light the therapeutic potential of targeting TIM3 in this, and potentially other, human autoimmune diseases. Furthermore, the demonstration that TIM3 can synergize with TLRs to promote inflammatory responses raises the possibility that TIM3 agonists could be used as adjuvants in vaccines.

Concluding remarksSince the initial discovery of the TIM proteins, major progress has been made in identifying their ligands and their biological functions in the immune system (FIG. 2; 

TABLe 1). It is now clear that the expression of TIM molecules is not restricted to T cells; this not only poses challenges to under-standing their functions, but also suggests that they regulate immune responses at multiple levels. with the recent elucida-tion of the crystal structures of the TIM molecules and identification of their ligands, the field has been opened up for the study of their functional biology and their role in human disease. Accumulating evidence

suggests that TIM3 negatively regulates TH1-cell responses and is dysregulated in multiple sclerosis. Similarly, TIM4, which seems to have a role in the clearance of apoptotic cells, might be involved in systemic autoimmune diseases such as systemic lupus erythemato-sus. Therefore, studying the role of this family of proteins in human disease might provide new targets for regulating autoimmune and inflammatory diseases.

Vijay K. Kuchroo, Valerie Dardalhon, Sheng Xiao and Ana C. Anderson are at the

Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, 77 Avenue Louis

Pasteur, Boston, Massachusetts 02115, USA.

Correspondence to V.K.K. e‑mail: vkuchroo@rics.bwh.harvard.edu

doi:10.1038/nri2366Published online 11 July 2008

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2.  Umetsu, S. E. et al. TIM‑1 induces T cell activation and inhibits the development of peripheral tolerance. Nature Immunol. 6, 447–454 (2005).

3.  Meyers, J. H. et al. TIM‑4 is the ligand for TIM‑1, and the TIM‑1–TIM‑4 interaction regulates T cell proliferation. Nature Immunol. 6, 455–464 (2005).

4.  Nakae, S., Iwakura, Y., Suto, H. & Galli, S. J. Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL‑17. J. Leukoc. Biol. 81, 1258–1268 (2007).

5.  Sizing, I. D. et al. Epitope‑dependent effect of anti‑murine TIM‑1 monoclonal antibodies on T cell activity and lung immune responses. J. Immunol. 178, 2249–2261 (2007).

6.  de Souza, A. J., Oriss, T. B., O’Malley, K. J., Ray, A. & Kane, L. P. T cell Ig and mucin 1(Tim‑1) is expressed on in vivo‑activated T cells and provides a costimulatory signal for T cell activation. Proc. Natl Acad. Sci. USA 102, 17113–17118 (2005).

7.  Degauque, N. et al. Immunostimulatory Tim‑1 specific antibody deprograms Tregs and prevents transplant tolerance in mice. J. Clin. Invest. 118, 735–741 (2008).

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9.  Ueno, T. et al. The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model. J. Clin. Invest. 118, 742–751 (2008).

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11.  Chakravarti, S. et al. TIM‑2 regulates T helper type 2 responses and autoimmunity. J. Exp. Med. 202, 437–444 (2005).

12.  Kumanogoh, A. et al. Class IV semaphorin Sema4A enhances T‑cell activation and interacts with Tim‑2. Nature 419, 629–633 (2002).

13.  Kumanogoh, A. et al. Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A‑deficient mice. Immunity 22, 305–316 (2005).

14.  Rennert, P. D. et al. T cell, Ig domain‑2 gene‑deficient mice reveal a novel mechanism for the regulation of Th2 immune responses and airway inflammation. J. Immunol. 177, 4311–4321 (2006).

15.  Knickelbein, J. E., de Souza, A. J., Tosti, R., Narayan, P. & Kane, L. P. Cutting Edge: inhibition of T cell activation by Tim‑2. J. Immunol. 177, 4966–4970 (2006).

16.  Rodriguez‑Manzanet, R. et al. TIM‑4 expressed on APCs induces T cell expansion and survival. J. Immunol. 180, 4706–4713 (2008).

17.  Mizui, M. et al. Bimodal regulation of T cell‑mediated immune responses by TIM‑4. Int. Immunol. 20, 695–708 (2008).

18.  Monney, L. et al. Th1‑specific cell surface protein Tim‑3 regulates macrophage activation and severity of an autoimmune disease. Nature 415, 536–541 (2002).

19.  Zhu, C. et al. The Tim‑3 ligand galectin‑9 negatively regulates T helper type 1 immunity. Nature Immunol. 6, 1245–1252 (2005).

20.  Anderson, A. C. et al. Promotion of tissue inflammation by the immune receptor Tim‑3 expressed on innate immune cells. Science 318, 1141–1143 (2007).

21.  Cao, E. et al. T cell immunoglobulin mucin‑3 crystal structure reveals a novel ligand binding surface. Immunity 26, 311–321 (2007).

22.  Santiago, C. et al. Structures of T cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family. Immunity 26, 299–310 (2007).

23.  Santiago, C. et al. Structures of T cell immunoglobulin mucin protein 4 show a metal‑ion‑dependent ligand binding site where phosphatidylserine binds. Immunity 27, 941–945 (2007).

24.  Miyanishi, M. et al. Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435–439 (2007).

25.  Kobayashi, N. et al. TIM‑1 and TIM‑4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27, 927–940 (2007).

26.  Khademi, M. et al. T cell Ig‑ and mucin‑domain containing molecule‑3 (TIM‑3) and TIM‑1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid‑derived mononuclear cells in multiple sclerosis. J. Immunol. 172, 7169–7176 (2004).

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28.  Yang, L., Anderson, D. E., Kuchroo, J. & Hafler, D. A. Lack of TIM‑3 immunoregulation in multiple sclerosis. J. Immunol. 180, 4409–4414 (2008).

DATABASESentrez gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geneCTLA4 | FoXP3 | galectin-9 | HAVCR1 | Havcr1 | HAVCR2 | Havcr2 | IFNγ | IL-4 | Timd2 | TIMD4 | Timd4

FURTHER INFORMATIONTheKuchroolaboratoryhomepage:http://kuchroo-lab.bwh.harvard.edu

AlllinKsAreAcTiveinTheonlinepdf

Table 1 | Known functions of TIM proteins

Timprotein

expression function refs

TIM1 Activated T cells; TH2 cells (high levels)

regulates TH2-cell responses 2–10

regulates pathogenic TH1- and TH17-cell responses 7,9

regulates Treg-cell suppressive capacity 7,9

role in TCr signalling 8,10

TIM2 TH2 cells Negative regulator of TH2-cell responses 11–15

TIM3 TH1 cells; DCs Negative regulator of TH1-cell responses by interacting with galectin-9

18,19

synergizes with TLr signalling to induce inflammation 20

TIM4 APCs Provides co-stimulation to promote T-cell proliferation and survival

3,16

Inhibits activation of naive T cells but not pre-activated T cells

17

Possible role in clearance of apoptotic cells by binding phosphatidylserine

23–25

APCs, antigen-presenting cells; DCs, dendritic cells; TCr, T-cell receptor; TH2 cells, T helper 2 cells; TIM, T-cell immunoglobulin domain and mucin domain; TLr, Toll-like receptor; Treg cell, regulatory T cell.

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