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TIM-3 and Its Regulatory Role in Immune Responses

  • Chen Zhu
  • Ana C. Anderson
  • Vijay K. Kuchroo
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 350)

Abstract

T cell immunoglobulin mucin-(TIM)-3 was first identified as a molecule specifically expressed on IFN-γ-secreting CD4+ T helper 1 (Th1) and CD8+ T cytotoxic (Tc1) cells in both mice and humans. TIM-3 acts as a negative regulator of Th1/Tc1 cell function by triggering cell death upon interaction with its ligand, galectin-9. This negative regulatory function of TIM-3 has now been expanded to include its involvement in establishing and/or maintaining a state of T cell dysfunction or “exhaustion” observed in chronic viral diseases. In addition, it is now appreciated that TIM-3 has other ligands and is expressed on other cell types, where it may function differently. Given that an increasing body of data support an important role for TIM-3 in both autoimmune and chronic inflammatory diseases in humans, deciphering the function of TIM-3 on different cell types during different immune conditions and how these can be regulated will be critical for harnessing the therapeutic potential of TIM-3 for the treatment of disease.

Keywords

Human Immunodeficiency Virus Experimental Autoimmune Encephalomyelitis Multiple Sclerosis Patient Chronic Viral Infection Apoptotic Cell Uptake 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Anderson AC, Anderson DE, Bregoli L, Hastings WD, Kassam N, Lei C, Chandwaskar R, Karman J, Su EW, Hirashima M et al (2007) Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 318:1141–1143PubMedCrossRefGoogle Scholar
  2. Anderson AC, Lord GM, Dardalhon V, Lee DH, Sabatos-Peyton CA, Glimcher LH, Kuchroo VK (2010) T-bet, a Th1 transcription factor regulates the expression of Tim-3. Eur J Immunol 40:859–866PubMedCrossRefGoogle Scholar
  3. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–687PubMedCrossRefGoogle Scholar
  4. Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg HC, Blum HE, Thimme R (2006) Expression of the interleukin-7 receptor alpha chain (CD127) on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J Virol 80:3532–3540PubMedCrossRefGoogle Scholar
  5. Bork P, Holm L, Sander C (1994) The immunoglobulin fold. Structural classification, sequence patterns and common core. J Mol Biol 242:309–320PubMedGoogle Scholar
  6. Butterfield RJ, Sudweeks JD, Blankenhorn EP, Korngold R, Marini JC, Todd JA, Roper RJ, Teuscher C (1998) New genetic loci that control susceptibility and symptoms of experimental allergic encephalomyelitis in inbred mice. J Immunol 161:1860–1867PubMedGoogle Scholar
  7. Cao E, Zang X, Ramagopal UA, Mukhopadhaya A, Fedorov A, Fedorov E, Zencheck WD, Lary JW, Cole JL, Deng H et al (2007) T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface. Immunity 26:311–321PubMedCrossRefGoogle Scholar
  8. Chae SC, Park YR, Lee YC, Lee JH, Chung HT (2004a) The association of TIM-3 gene polymorphism with atopic disease in Korean population. Hum Immunol 65:1427–1431PubMedCrossRefGoogle Scholar
  9. Chae SC, Park YR, Shim SC, Yoon KS, Chung HT (2004b) The polymorphisms of Th1 cell surface gene Tim-3 are associated in a Korean population with rheumatoid arthritis. Immunol Lett 95:91–95PubMedCrossRefGoogle Scholar
  10. Chen Y, Langrish CL, McKenzie B, Joyce-Shaikh B, Stumhofer JS, McClanahan T, Blumenschein W, Churakovsa T, Low J, Presta L et al (2006) Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 116:1317–1326PubMedCrossRefGoogle Scholar
  11. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C et al (2006) PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350–354PubMedCrossRefGoogle Scholar
  12. DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, Karisola P, Pichavant M, Kaplan GG, Umetsu DT et al (2010) T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol 184:1918–1930PubMedCrossRefGoogle Scholar
  13. Frisancho-Kiss S, Nyland JF, Davis SE, Barrett MA, Gatewood SJ, Njoku DB, Cihakova D, Silbergeld EK, Rose NR, Fairweather D (2006) Cutting edge: T cell Ig mucin-3 reduces inflammatory heart disease by increasing CTLA-4 during innate immunity. J Immunol 176:6411–6415PubMedGoogle Scholar
  14. Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S, McMahon BJ, Castelblanco N, Kuchroo V, Gretch DR, Rosen HR (2009) Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol 83:9122–9130PubMedCrossRefGoogle Scholar
  15. Grattan M, Mi QS, Meagher C, Delovitch TL (2002) Congenic mapping of the diabetogenic locus Idd4 to a 5.2-cM region of chromosome 11 in NOD mice: identification of two potential candidate subloci. Diabetes 51:215–223PubMedCrossRefGoogle Scholar
  16. Graves PE, Siroux V, Guerra S, Klimecki WT, Martinez FD (2005) Association of atopy and eczema with polymorphisms in T-cell immunoglobulin domain and mucin domain-IL-2-inducible T-cell kinase gene cluster in chromosome 5 q 33. J Allergy Clin Immunol 116:650–656PubMedCrossRefGoogle Scholar
  17. Hastings WD, Anderson DE, Kassam N, Koguchi K, Greenfield EA, Kent SC, Zheng XX, Strom TB, Hafler DA, Kuchroo VK (2009) TIM-3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines. Eur J Immunol 39:2492–2501PubMedCrossRefGoogle Scholar
  18. Huang X, Bai X, Cao Y, Wu J, Huang M, Tang D, Tao S, Zhu T, Liu Y, Yang Y et al (2010) Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion. J Exp Med 207:505–520PubMedCrossRefGoogle Scholar
  19. Imaizumi T, Kumagai M, Sasaki N, Kurotaki H, Mori F, Seki M, Nishi N, Fujimoto K, Tanji K, Shibata T et al (2002) Interferon-gamma stimulates the expression of galectin-9 in cultured human endothelial cells. J Leukoc Biol 72:486–491PubMedGoogle Scholar
  20. Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, Wong JC, Satkunarajah M, Schweneker M, Chapman JM et al (2008) Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med 205:2763–2779PubMedCrossRefGoogle Scholar
  21. Khademi M, Illes Z, Gielen AW, Marta M, Takazawa N, Baecher-Allan C, Brundin L, Hannerz J, Martin C, Harris RA et al (2004) 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 172:7169–7176PubMedGoogle Scholar
  22. Klenerman P, Hill A (2005) T cells and viral persistence: lessons from diverse infections. Nat Immunol 6:873–879PubMedCrossRefGoogle Scholar
  23. Klibi J, Niki T, Riedel A, Pioche-Durieu C, Souquere S, Rubinstein E, Le Moulec S, Guigay J, Hirashima M, Guemira F et al (2009) Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells. Blood 113:1957–1966PubMedCrossRefGoogle Scholar
  24. Koguchi K, Anderson DE, Yang L, O'Connor KC, Kuchroo VK, Hafler DA (2006) Dysregulated T cell expression of TIM3 in multiple sclerosis. J Exp Med 203:1413–1418PubMedCrossRefGoogle Scholar
  25. Kono DH, Burlingame RW, Owens DG, Kuramochi A, Balderas RS, Balomenos D, Theofilopoulos AN (1994) Lupus susceptibility loci in New Zealand mice. Proc Natl Acad Sci USA 91:10168–10172PubMedCrossRefGoogle Scholar
  26. McIntire JJ, Umetsu SE, Akbari O, Potter M, Kuchroo VK, Barsh GS, Freeman GJ, Umetsu DT, DeKruyff RH (2001) Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol 2:1109–1116PubMedCrossRefGoogle Scholar
  27. Mengshol JA, Golden-Mason L, Arikawa T, Smith M, Niki T, McWilliams R, Randall JA, McMahan R, Zimmerman MA, Rangachari M, Dobrinskikh E, Busson P, Polyak SJ, Hirashima M, Rosen HR (2010) A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection. PLoS One 5(3):e9504Google Scholar
  28. Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura, Nagata S (2007) Identification of Tim4 as a phosphatidylserine receptor. Nature 450:435–439PubMedCrossRefGoogle Scholar
  29. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA et al (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415:536–541PubMedCrossRefGoogle Scholar
  30. Nagahara K, Arikawa T, Oomizu S, Kontani K, Nobumoto A, Tateno H, Watanabe K, Niki T, Katoh S, Miyake M et al (2008) Galectin-9 increases Tim-3+ dendritic cells and CD8+ T cells and enhances antitumor immunity via galectin-9-Tim-3 interactions. J Immunol 181:7660–7669PubMedGoogle Scholar
  31. Nakae S, Iikura M, Suto H, Akiba H, Umetsu DT, Dekruyff RH, Saito H, Galli SJ (2007) TIM-1 and TIM-3 enhancement of Th2 cytokine production by mast cells. Blood 110:2565–2568PubMedCrossRefGoogle Scholar
  32. Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, Azuma M, Yagita H, Okumura K (2009) Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood 113:3821–3830PubMedCrossRefGoogle Scholar
  33. Niwa H, Satoh T, Matsushima Y, Hosoya K, Saeki K, Niki T, Hirashima M, Yokozeki H (2009) Stable form of galectin-9, a Tim-3 ligand, inhibits contact hypersensitivity and psoriatic reactions: a potent therapeutic tool for Th1- and/or Th17-mediated skin inflammation. Clin Immunol 132:184–194PubMedCrossRefGoogle Scholar
  34. Oikawa T, Kamimura Y, Akiba H, Yagita H, Okumura K, Takahashi H, Zeniya M, Tajiri H, Azuma M (2006) Preferential involvement of Tim-3 in the regulation of hepatic CD8+ T cells in murine acute graft-versus-host disease. J Immunol 177:4281–4287PubMedGoogle Scholar
  35. Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, Precopio ML, Schacker T, Roederer M, Douek DC et al (2006) PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 203:2281–2292PubMedCrossRefGoogle Scholar
  36. Rabinovich GA, Toscano MA (2009) Turning 'sweet' on immunity: galectin-glycan interactions in immune tolerance and inflammation. Nat Rev Immunol 9:338–352PubMedCrossRefGoogle Scholar
  37. Sabatos CA, Chakravarti S, Cha E, Schubart A, Sanchez-Fueyo A, Zheng XX, Coyle AJ, Strom TB, Freeman GJ, Kuchroo VK (2003) Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol 4:1102–1110PubMedCrossRefGoogle Scholar
  38. Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, Manlongat N, Bender O, Kamradt T, Kuchroo VK et al (2003) Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol 4:1093–1101PubMedCrossRefGoogle Scholar
  39. Santiago C, Ballesteros A, Martinez-Munoz L, Mellado M, Kaplan GG, Freeman GJ, Casasnovas JM (2007a) Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds. Immunity 27:941–951PubMedCrossRefGoogle Scholar
  40. Santiago C, Ballesteros A, Tami C, Martinez-Munoz L, Kaplan GG, Casasnovas JM (2007b) Structures of T cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family. Immunity 26:299–310PubMedCrossRefGoogle Scholar
  41. Sehrawat S, Suryawanshi A, Hirashima M, Rouse BT (2009) Role of Tim-3/galectin-9 inhibitory interaction in viral-induced immunopathology: shifting the balance toward regulators. J Immunol 182:3191–3201PubMedCrossRefGoogle Scholar
  42. Seki M, Oomizu S, Sakata KM, Sakata A, Arikawa T, Watanabe K, Ito K, Takeshita K, Niki T, Saita N et al (2008) Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol 127:78–88PubMedCrossRefGoogle Scholar
  43. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669PubMedCrossRefGoogle Scholar
  44. Takamura S, Tsuji-Kawahara S, Yagita H, Akiba H, Sakamoto M, Chikaishi T, Kato M, Miyazawa M (2010) Premature terminal exhaustion of Friend virus-specific effector CD8+ T cells by rapid induction of multiple inhibitory receptors. J Immunol 184:4696–4707Google Scholar
  45. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, Boulassel MR, Delwart E, Sepulveda H, Balderas RS et al (2006) Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12:1198–1202PubMedCrossRefGoogle Scholar
  46. Urbani S, Amadei B, Tola D, Massari M, Schivazappa S, Missale G, Ferrari C (2006) PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 80:11398–11403PubMedCrossRefGoogle Scholar
  47. van de Weyer PS, Muehlfeit M, Klose C, Bonventre JV, Walz G, Kuehn EW (2006) A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9. Biochem Biophys Res Commun 351:571–576PubMedCrossRefGoogle Scholar
  48. Wang F, He W, Zhou H, Yuan J, Wu K, Xu L, Chen ZK (2007) The Tim-3 ligand galectin-9 negatively regulates CD8+ alloreactive T cell and prolongs survival of skin graft. Cell Immunol 250:68–74PubMedCrossRefGoogle Scholar
  49. Wiener Z, Kohalmi B, Pocza P, Jeager J, Tolgyesi G, Toth S, Gorbe E, Papp Z, Falus A (2007) TIM-3 is expressed in melanoma cells and is upregulated in TGF-beta stimulated mast cells. J Invest Dermatol 127:906–914PubMedCrossRefGoogle Scholar
  50. Wilker PR, Sedy JR, Grigura V, Murphy TL, Murphy KM (2007) Evidence for carbohydrate recognition and homotypic and heterotypic binding by the TIM family. Int Immunol 19:763–773PubMedCrossRefGoogle Scholar
  51. Yang L, Anderson DE, Kuchroo J, Hafler DA (2008) Lack of TIM-3 immunoregulation in multiple sclerosis. J Immunol 180:4409–4414PubMedGoogle Scholar
  52. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, Ahmed R (1998) Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188:2205–2213PubMedCrossRefGoogle Scholar
  53. Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK (2005) The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 6:1245–1252PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Center for Neurologic DiseasesBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA

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