Immunologic Research

, Volume 59, Issue 1–3, pp 56–65 | Cite as

Regulation of T cell responses by the receptor molecule Tim-3

  • Jacob V. Gorman
  • John D. ColganEmail author


Tim-3 is a member of the T cell immunoglobulin and mucin domain (Tim) family of proteins, which are expressed by several cell types in the immune system, including CD4 and CD8 T cells activated under certain conditions. These molecules are generally thought to act as receptors for multiple ligands and thus to function by engaging intracellular signaling pathways in a ligand-dependent manner. In recent years, the function of the Tim-3 protein has been studied in some detail, particularly with respect to its role in the regulation of CD4 and CD8 T cell responses. Here, we review the structural features of Tim-3, known ligands for this molecule and the links established between Tim-3 and signal transduction pathways. In addition, we review the current literature regarding the role of Tim-3 in the regulation of effector responses by CD4 and CD8 T cells. Overall, findings published thus far strongly support the conclusion that Tim-3 functions to inhibit T cell responses, particularly under conditions involving chronic stimulation. Conversely, some reports have provided evidence that Tim-3 can stimulate T cells under conditions involving acute stimulation, suggesting that the role of Tim-3 may vary depending on context. Further study of Tim-3 is likely to advance our understanding of how CD4 and CD8 T cell responses are regulated and could uncover novel approaches for manipulating T cell function for therapeutic benefit.


T cells Tim protein family Surface receptor Signal transduction Immune system regulation 



This work was supported by the following grants from the National Institutes: T32 AI007485 (to J.V.G.); R01AI054821 and R01AI093737 (to J.D.C.).

Conflict of interest

The authors declare that they have no conflict of interest


  1. 1.
    Kane LP. T cell Ig and mucin domain proteins and immunity. J Immunol. 2010;184(6):2743–9.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Freeman GJ, Casasnovas JM, Umetsu DT, DeKruyff RH. TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev. 2010;235(1):172–89.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Zhu C, Anderson AC, Kuchroo VK. TIM-3 and its regulatory role in immune responses. Curr Top Microbiol Immunol. 2011;350:1–15.PubMedGoogle Scholar
  4. 4.
    Han G, Chen G, Shen B, Li Y. Tim-3: an activation marker and activation limiter of innate immune cells. Front Immunol. 2013;4:449.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Bailly V, Zhang Z, Meier W, Cate R, Sanicola M, Bonventre JV. Shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration. J Biol Chem. 2002;277(42):39739–48.PubMedCrossRefGoogle Scholar
  6. 6.
    Sabatos CA, Chakravarti S, Cha E, Schubart A, Sanchez-Fueyo A, Zheng XX, et al. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol. 2003;4(11):1102–10.PubMedCrossRefGoogle Scholar
  7. 7.
    Geng H, Zhang GM, Li D, Zhang H, Yuan Y, Zhu HG, et al. Soluble form of T cell Ig mucin 3 is an inhibitory molecule in T cell-mediated immune response. J Immunol. 2006;176(3):1411–20.PubMedCrossRefGoogle Scholar
  8. 8.
    Moller-Hackbarth K, Dewitz C, Schweigert O, Trad A, Garbers C, Rose-John S, et al. A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are major sheddases of T cell immunoglobulin and mucin domain 3 (Tim-3). J Biol Chem. 2013;288(48):34529–44.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Schweigert O, Dewitz C, Moller-Hackbarth K, Trad A, Garbers C, Rose-John S, et al. Soluble T cell immunoglobulin and mucin domain (TIM)-1 and -4 generated by a disintegrin and metalloprotease (ADAM)-10 and -17 bind to phosphatidylserine. Biochim Biophys Acta. 2014;1843(2):275–87.PubMedCrossRefGoogle Scholar
  10. 10.
    Meyers JH, Sabatos CA, Chakravarti S, Kuchroo VK. The TIM gene family regulates autoimmune and allergic diseases. Trends Mol Med. 2005;11(8):362–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Anderson AC, Anderson DE. TIM-3 in autoimmunity. Curr Opin Immunol. 2006;18(6):665–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Lee J, Oh JM, Hwang JW, Ahn JK, Bae EK, Won J, et al. Expression of human TIM-3 and its correlation with disease activity in rheumatoid arthritis. Scand J Rheumatol. 2011;40(5):334–40.PubMedCrossRefGoogle Scholar
  13. 13.
    de Souza AJ, Oriss TB, O’Malley KJ, Ray A, Kane LP. 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. 2005;102(47):17113–8.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    de Souza AJ, Oak JS, Jordanhazy R, DeKruyff RH, Fruman DA, Kane LP. T cell Ig and mucin domain-1-mediated T cell activation requires recruitment and activation of phosphoinositide 3-kinase. J Immunol. 2008;180(10):6518–26.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    van de Weyer PS, Muehlfeit M, Klose C, Bonventre JV, Walz G, Kuehn EW. A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9. Biochem Biophys Res Commun. 2006;351(2):571–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Lee J, Su EW, Zhu C, Hainline S, Phuah J, Moroco JA, et al. Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways. Mol Cell Biol. 2011;31(19):3963–74.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Curtiss ML, Hostager BS, Stepniak E, Singh M, Manhica N, Knisz J, et al. Fyn binds to and phosphorylates T cell immunoglobulin and mucin domain-1 (Tim-1). Mol Immunol. 2011;48(12–13):1424–31.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Binne LL, Scott ML, Rennert PD. Human TIM-1 associates with the TCR complex and up-regulates T cell activation signals. J Immunol. 2007;178(7):4342–50.PubMedCrossRefGoogle Scholar
  19. 19.
    Clayton KL, Haaland MS, Douglas-Vail MB, Mujib S, Chew GM, Ndhlovu LC, et al. T cell Ig and mucin domain-containing protein 3 is recruited to the immune synapse, disrupts stable synapse formation, and associates with receptor phosphatases. J Immunol. 2014;192(2):782–91.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Rodriguez-Manzanet R, Meyers JH, Balasubramanian S, Slavik J, Kassam N, Dardalhon V, et al. TIM-4 expressed on APCs induces T cell expansion and survival. J Immunol. 2008;180(7):4706–13.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Umetsu SE, Lee WL, McIntire JJ, Downey L, Sanjanwala B, Akbari O, et al. TIM-1 induces T cell activation and inhibits the development of peripheral tolerance. Nat Immunol. 2005;6(5):447–54.PubMedCrossRefGoogle Scholar
  22. 22.
    Anderson AC, Anderson DE, Bregoli L, Hastings WD, Kassam N, Lei C, et al. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science. 2007;318(5853):1141–3.PubMedCrossRefGoogle Scholar
  23. 23.
    Mariat C, Degauque N, Balasubramanian S, Kenny J, DeKruyff RH, Umetsu DT, et al. Tim-1 signaling substitutes for conventional signal 1 and requires costimulation to induce T cell proliferation. J Immunol. 2009;182(3):1379–85.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Kim HS, Kim HS, Lee CW, Chung DH. T cell Ig domain and mucin domain 1 engagement on invariant NKT cells in the presence of TCR stimulation enhances IL-4 production but inhibits IFN-gamma production. J Immunol. 2010;184(8):4095–106.PubMedCrossRefGoogle Scholar
  25. 25.
    Rangachari M, Zhu C, Sakuishi K, Xiao S, Karman J, Chen A, et al. Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion. Nat Med. 2012;18(9):1394–400.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Rodriguez-Manzanet R, DeKruyff R, Kuchroo VK, Umetsu DT. The costimulatory role of TIM molecules. Immunol Rev. 2009;229(1):259–70.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Kaplan G, Totsuka A, Thompson P, Akatsuka T, Moritsugu Y, Feinstone SM. Identification of a surface glycoprotein on African green monkey kidney cells as a receptor for hepatitis A virus. EMBO J. 1996;15(16):4282–96.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415(6871):536–41.PubMedCrossRefGoogle Scholar
  29. 29.
    Cao E, Zang X, Ramagopal UA, Mukhopadhaya A, Fedorov A, Fedorov E, et al. T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface. Immunity. 2007;26(3):311–21.PubMedCrossRefGoogle Scholar
  30. 30.
    Santiago C, Ballesteros A, Martinez-Munoz L, Mellado M, Kaplan GG, Freeman GJ, et al. Structures of T cell immunoglobulin mucin protein 4 show a metal-ion-dependent ligand binding site where phosphatidylserine binds. Immunity. 2007;27(6):941–51.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Santiago C, Ballesteros A, Tami C, Martinez-Munoz L, Kaplan GG, Casasnovas JM. Structures of T cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family. Immunity. 2007;26(3):299–310.PubMedCrossRefGoogle Scholar
  32. 32.
    DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, et al. T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol. 2010;184(4):1918–30.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6(12):1245–52.PubMedCrossRefGoogle Scholar
  34. 34.
    Rabinovich GA, Ilarregui JM. Conveying glycan information into T-cell homeostatic programs: a challenging role for galectin-1 in inflammatory and tumor microenvironments. Immunol Rev. 2009;230(1):144–59.PubMedCrossRefGoogle Scholar
  35. 35.
    Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, Azuma M, et al. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood. 2009;113(16):3821–30.PubMedCrossRefGoogle Scholar
  36. 36.
    Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol. 2012;13(9):832–42.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Sehrawat S, Reddy PB, Rajasagi N, Suryawanshi A, Hirashima M, Rouse BT. Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response. PLoS Pathog. 2010;6(5):e1000882.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Su EW, Bi S, Kane LP. Galectin-9 regulates T helper cell function independently of Tim-3. Glycobiology. 2011;21(10):1258–65.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Leitner J, Rieger A, Pickl WF, Zlabinger G, Grabmeier-Pfistershammer K, Steinberger P. TIM-3 does not act as a receptor for galectin-9. PLoS Pathog. 2013;9(3):e1003253.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Wilker PR, Sedy JR, Grigura V, Murphy TL, Murphy KM. Evidence for carbohydrate recognition and homotypic and heterotypic binding by the TIM family. Int Immunol. 2007;19(6):763–73.PubMedCrossRefGoogle Scholar
  41. 41.
    Lee MJ, Woo MY, Chwae YJ, Kwon MH, Kim K, Park S. Down-regulation of interleukin-2 production by CD4(+) T cells expressing TIM-3 through suppression of NFAT dephosphorylation and AP-1 transcription. Immunobiology. 2012;217(10):986–95.PubMedCrossRefGoogle Scholar
  42. 42.
    Frisancho-Kiss S, Davis SE, Nyland JF, Frisancho JA, Cihakova D, Barrett MA, et al. Cutting edge: cross-regulation by TLR4 and T cell Ig mucin-3 determines sex differences in inflammatory heart disease. J Immunol. 2007;178(11):6710–4.PubMedCrossRefGoogle Scholar
  43. 43.
    Yang X, Jiang X, Chen G, Xiao Y, Geng S, Kang C, et al. T cell Ig mucin-3 promotes homeostasis of sepsis by negatively regulating the TLR response. J Immunol. 2013;190(5):2068–79.PubMedCrossRefGoogle Scholar
  44. 44.
    Zhang Y, Ma CJ, Wang JM, Ji XJ, Wu XY, Moorman JP, et al. Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14 + monocytes. J Leukocyte Biol. 2012;91(2):189–96.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Ju Y, Hou N, Meng J, Wang X, Zhang X, Zhao D, et al. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B. J Hepatol. 2010;52(3):322–9.PubMedCrossRefGoogle Scholar
  46. 46.
    McIntire JJ, Umetsu SE, Akbari O, Potter M, Kuchroo VK, Barsh GS, et al. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol. 2001;2(12):1109–16.PubMedCrossRefGoogle Scholar
  47. 47.
    Lee SY, Goverman JM. The influence of T cell Ig mucin-3 signaling on central nervous system autoimmune disease is determined by the effector function of the pathogenic T cells. J Immunol. 2013;190(10):4991–9.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, et al. Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol. 2003;4(11):1093–101.PubMedCrossRefGoogle Scholar
  49. 49.
    Li X, Chen G, Li Y, Wang R, Wang L, Lin Z, et al. Involvement of T cell Ig Mucin-3 (Tim-3) in the negative regulation of inflammatory bowel disease. Clin Immunol. 2010;134(2):169–77.PubMedCrossRefGoogle Scholar
  50. 50.
    Schroll A, Eller K, Huber JM, Theurl IM, Wolf AM, Weiss G, et al. Tim3 is upregulated and protective in nephrotoxic serum nephritis. Am J Pathol. 2010;176(4):1716–24.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Shi F, Guo X, Jiang X, Zhou P, Xiao Y, Zhou T, et al. Dysregulated Tim-3 expression and its correlation with imbalanced CD4 helper T cell function in ulcerative colitis. Clin Immunol. 2012;145(3):230–40.PubMedCrossRefGoogle Scholar
  52. 52.
    Kanzaki M, Wada J, Sugiyama K, Nakatsuka A, Teshigawara S, Murakami K, et al. Galectin-9 and T cell immunoglobulin mucin-3 pathway is a therapeutic target for type 1 diabetes. Endocrinology. 2012;153(2):612–20.PubMedCrossRefGoogle Scholar
  53. 53.
    Foks AC, Ran IA, Wasserman L, Frodermann V, Ter Borg MN, de Jager SC, et al. T-cell immunoglobulin and mucin domain 3 acts as a negative regulator of atherosclerosis. Arterioscler Thromb Vasc Biol. 2013;33(11):2558–65.PubMedCrossRefGoogle Scholar
  54. 54.
    Kaneyama T, Tomiki H, Tsugane S, Inaba Y, Ichikawa M, Akiba H, et al. The TIM-3 pathway ameliorates Theiler’s murine encephalomyelitis virus-induced demyelinating disease. Int Immunol. 2014;. doi: 10.1093/intimm/dxt056.PubMedGoogle Scholar
  55. 55.
    Boenisch O, D’Addio F, Watanabe T, Elyaman W, Magee CN, Yeung MY, et al. TIM-3: a novel regulatory molecule of alloimmune activation. J Immunol. 2010;185(10):5806–19.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Veenstra RG, Taylor PA, Zhou Q, Panoskaltsis-Mortari A, Hirashima M, Flynn R, et al. Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells. Blood. 2012;120(3):682–90.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Fukushima A, Sumi T, Fukuda K, Kumagai N, Nishida T, Akiba H, et al. Antibodies to T-cell Ig and mucin domain-containing proteins (Tim)-1 and -3 suppress the induction and progression of murine allergic conjunctivitis. Biochem Biophys Res Commun. 2007;353(1):211–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Kearley J, McMillan SJ, Lloyd CM. Th2-driven, allergen-induced airway inflammation is reduced after treatment with anti-Tim-3 antibody in vivo. J Exp Med. 2007;204(6):1289–94.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Gupta S, Thornley TB, Gao W, Larocca R, Turka LA, Kuchroo VK, et al. Allograft rejection is restrained by short-lived TIM-3+ PD-1+ Foxp3+ Tregs. J Clin Invest. 2012;122(7):2395–404.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Gao X, Zhu Y, Li G, Huang H, Zhang G, Wang F, et al. TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS ONE. 2012;7(2):e30676.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Seki M, Oomizu S, Sakata KM, Sakata A, Arikawa T, Watanabe K, et al. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol. 2008;127(1):78–88.PubMedCrossRefGoogle Scholar
  62. 62.
    Wang F, He W, Yuan J, Wu K, Zhou H, Zhang W, et al. Activation of Tim-3-Galectin-9 pathway improves survival of fully allogeneic skin grafts. Transpl Immunol. 2008;19(1):12–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Chou FC, Kuo CC, Wang YL, Lin MH, Yen BL, Chang DM, et al. Overexpression of Galectin-9 in islets prolongs grafts survival via downregulation of Th1 responses. Cell Transpl. 2012;22(11):2135–45.CrossRefGoogle Scholar
  64. 64.
    Sakai K, Kawata E, Ashihara E, Nakagawa Y, Yamauchi A, Yao H, et al. Galectin-9 ameliorates acute GVH disease through the induction of T-cell apoptosis. Eur J Immunol. 2011;41(1):67–75.PubMedCrossRefGoogle Scholar
  65. 65.
    Sehrawat S, Suryawanshi A, Hirashima M, Rouse BT. Role of Tim-3/galectin-9 inhibitory interaction in viral-induced immunopathology: shifting the balance toward regulators. J Immunol. 2009;182(5):3191–201.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Niwa H, Satoh T, Matsushima Y, Hosoya K, Saeki K, Niki T, et al. 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. 2009;132(2):184–94.PubMedCrossRefGoogle Scholar
  67. 67.
    Dardalhon V, Anderson AC, Karman J, Apetoh L, Chandwaskar R, Lee DH, et al. Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b + Ly-6G + myeloid cells. J Immunol. 2010;185(3):1383–92.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Kojima K, Arikawa T, Saita N, Goto E, Tsumura S, Tanaka R, et al. Galectin-9 attenuates acute lung injury by expanding CD14- plasmacytoid dendritic cell-like macrophages. Am J Resp Crit Care. 2011;184(3):328–39.CrossRefGoogle Scholar
  69. 69.
    Wang F, Xu J, Liao Y, Wang Y, Liu C, Zhu X, et al. Tim-3 ligand galectin-9 reduces IL-17 level and accelerates Klebsiella pneumoniae infection. Cell Immunol. 2011;269(1):22–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Lv K, Zhang Y, Zhang M, Zhong M, Suo Q. Galectin-9 ameliorates Con A-induced hepatitis by inducing CD4(+)CD25(low/int) effector T-Cell apoptosis and increasing regulatory T cell number. PLoS ONE. 2012;7(10):e48379.PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Mengshol JA, Golden-Mason L, Arikawa T, Smith M, Niki T, McWilliams R, et al. A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection. PLoS ONE. 2010;5(3):e9504.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Bi S, Hong PW, Lee B, Baum LG. Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci USA. 2011;108(26):10650–5.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Qi Y, Song XR, Shen JL, Xu YH, Shen Q, Luo QL, et al. Tim-2 up-regulation and galectin-9-Tim-3 pathway activation in Th2-biased response in Schistosoma japonicum infection in mice. Immunol Lett. 2012;144(1–2):60–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, et al. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med. 2008;205(12):2763–79.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Kassu A, Marcus RA, D’Souza MB, Kelly-McKnight EA, Golden-Mason L, Akkina R, et al. Regulation of virus-specific CD4 + T cell function by multiple costimulatory receptors during chronic HIV infection. J Immunol. 2010;185(5):3007–18.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S, McMahon BJ, et al. 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. 2009;83(18):9122–30.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Moorman JP, Wang JM, Zhang Y, Ji XJ, Ma CJ, Wu XY, et al. Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection. J Immunol. 2012;189(2):755–66.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Qiu Y, Chen J, Liao H, Zhang Y, Wang H, Li S, et al. Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions. PLoS Pathog. 2012;8(11):e1002984.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Ju Y, Hou N, Zhang XN, Zhao D, Liu Y, Wang JJ, et al. Blockade of Tim-3 pathway ameliorates interferon-gamma production from hepatic CD8+ T cells in a mouse model of hepatitis B virus infection. Cell Mol Immunol. 2009;6(1):35–43.PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Jin HT, Anderson AC, Tan WG, West EE, Ha SJ, Araki K, et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci USA. 2010;107(33):14733–8.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Cho JL, Roche MI, Sandall B, Brass AL, Seed B, Xavier RJ, et al. Enhanced Tim3 activity improves survival after influenza infection. J Immunol. 2012;189(6):2879–89.PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Sharma S, Sundararajan A, Suryawanshi A, Kumar N, Veiga-Parga T, Kuchroo VK, et al. T cell immunoglobulin and mucin protein-3 (Tim-3)/Galectin-9 interaction regulates influenza A virus-specific humoral and CD8 T-cell responses. Proc Natl Acad Sci USA. 2011;108(47):19001–6.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Cyktor JC, Carruthers B, Beamer GL, Turner J. Clonal expansions of CD8+T cells with IL-10 secreting capacity occur during chronic Mycobacterium tuberculosis infection. PLoS ONE. 2013;8(3):e58612.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Gorman JV, Starbeck-Miller G, Pham NL, Traver GL, Rothman PB, Harty JT, et al. Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection. J Immunol. 2014;192(7):3133–42.PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Vali B, Jones RB, Sakhdari A, Sheth PM, Clayton K, Yue FY, et al. HCV-specific T cells in HCV/HIV co-infection show elevated frequencies of dual Tim-3/PD-1 expression that correlate with liver disease progression. Eur J Immunol. 2010;40(9):2493–505.PubMedCrossRefGoogle Scholar
  87. 87.
    McMahan RH, Golden-Mason L, Nishimura MI, McMahon BJ, Kemper M, Allen TM, et al. Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J Clin Invest. 2010;120(12):4546–57.PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Wu W, Shi Y, Li J, Chen F, Chen Z, Zheng M. Tim-3 expression on peripheral T cell subsets correlates with disease progression in hepatitis B infection. Virol J. 2011;8:113.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Nebbia G, Peppa D, Schurich A, Khanna P, Singh HD, Cheng Y, et al. Upregulation of the Tim-3/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection. PLoS ONE. 2012;7(10):e47648.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Tandon R, Giret MT, Sengupta D, York VA, Wiznia AA, Rosenberg MG, et al. Age-related expansion of Tim-3 expressing T cells in vertically HIV-1 infected children. PLoS ONE. 2012;7(9):e45733.PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Kared H, Fabre T, Bedard N, Bruneau J, Shoukry NH. Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. PLoS Pathog. 2013;9(6):e1003422.PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Sumida K, Shimoda S, Iwasaka S, Hisamoto S, Kawanaka H, Akahoshi T, et al. Characteristics of splenic CD8 T cell exhaustion in patients with hepatitis C. Clin Exp Immunol. 2013;174(1):172–8.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207(10):2187–94.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207(10):2175–86.PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Baitsch L, Baumgaertner P, Devevre E, Raghav SK, Legat A, Barba L, et al. Exhaustion of tumor-specific CD8(+) T cells in metastases from melanoma patients. J Clin Invest. 2011;121(6):2350–60.PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Baitsch L, Legat A, Barba L, Fuertes Marraco SA, Rivals JP, Baumgaertner P, et al. Extended co-expression of inhibitory receptors by human CD8 T-cells depending on differentiation, antigen-specificity and anatomical localization. PLoS ONE. 2012;7(2):e30852.PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Li H, Wu K, Tao K, Chen L, Zheng Q, Lu X, et al. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology. 2012;56(4):1342–51.PubMedCrossRefGoogle Scholar
  98. 98.
    Afanasiev OK, Yelistratova L, Miller N, Nagase K, Paulson K, Iyer JG, et al. Merkel polyomavirus-specific T cells fluctuate with merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers. Clin Cancer Res. 2013;19(19):5351–60.PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Wu W, Shi Y, Li S, Zhang Y, Liu Y, Wu Y, et al. Blockade of Tim-3 signaling restores the virus-specific CD8(+) T-cell response in patients with chronic hepatitis B. Eur J Immunol. 2012;42(5):1180–91.PubMedCrossRefGoogle Scholar
  100. 100.
    Takamura S, Tsuji-Kawahara S, Yagita H, Akiba H, Sakamoto M, Chikaishi T, et al. Premature terminal exhaustion of friend virus-specific effector CD8+ T cells by rapid induction of multiple inhibitory receptors. J Immunol. 2010;184(9):4696–707.PubMedCrossRefGoogle Scholar
  101. 101.
    Dietze KK, Zelinskyy G, Liu J, Kretzmer F, Schimmer S, Dittmer U. Combining regulatory T cell depletion and inhibitory receptor blockade improves reactivation of exhausted virus-specific CD8(+) T cells and efficiently reduces chronic retroviral loads. PLoS Pathog. 2013;9(12):e1003798.PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Ngiow SF, von Scheidt B, Akiba H, Yagita H, Teng MW, Smyth MJ. Anti-TIM3 antibody promotes T cell IFN-gamma-mediated antitumor immunity and suppresses established tumors. Cancer Res. 2011;71(10):3540–51.PubMedCrossRefGoogle Scholar
  103. 103.
    Wang X, Cao Z, Jiang J, Li Y, Dong M, Ostrowski M, et al. Elevated expression of Tim-3 on CD8 T cells correlates with disease severity of pulmonary tuberculosis. J Infect. 2011;62(4):292–300.PubMedCrossRefGoogle Scholar
  104. 104.
    Callahan MK, Wolchok JD. At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J Leukocyte Biol. 2013;94(1):41–53.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Interdisciplinary Graduate Program in Immunology, Carver College of MedicineUniversity of IowaIowa CityUSA
  2. 2.Departments of Internal Medicine and Anatomy and Cell Biology, Carver College of MedicineUniversity of IowaIowa CityUSA

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