Emerging Tim-3 Functions in Antimicrobial and Tumor Immunity

Overview

Journal Trends Immunol

Specialty Allergy & Immunology

Date 2011 Jun 24

PMID 21697013

Citations 130

Authors

Kaori Sakuishi

Pushpa Jayaraman

Samuel M Behar

Ana C Anderson

Vijay K Kuchroo

Affiliations

Soon will be listed here.

Abstract

T cell immunoglobulin-3 (Tim-3) has been identified as a marker of differentiated interferon-γ-producing CD4(+) T helper type 1 and CD8(+) T cytotoxic type 1 cells. The interaction of Tim-3 with its ligand, galectin-9 (Gal-9), induces cell death, and in vivo blockade of this interaction results in exacerbated autoimmunity and abrogation of tolerance in experimental models, establishing Tim-3 as a negative regulatory molecule. Recent studies have uncovered additional mechanisms by which Tim-3 negatively regulates T cell responses, such as promoting the development of CD8(+) T cell exhaustion and inducing expansion of myeloid-derived suppressor cells. In contrast to this inhibitory effect on T cells, Tim-3-Gal-9 interaction promotes macrophage clearance of intracellular pathogens. Here, we focus on the emerging role for Tim-3 in tumor and antimicrobial immunity.

Citing Articles

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References

Barber D, Wherry E, Masopust D, Zhu B, Allison J, Sharpe A . Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2005; 439(7077):682-7. DOI: 10.1038/nature04444. View

Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg H, Blum H . 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. 2006; 80(7):3532-40. PMC: 1440406. DOI: 10.1128/JVI.80.7.3532-3540.2006. View

Curiel T, Wei S, Dong H, Alvarez X, Cheng P, Mottram P . Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. 2003; 9(5):562-7. DOI: 10.1038/nm863. View

Yamamoto R, Nishikori M, Kitawaki T, Sakai T, Hishizawa M, Tashima M . PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 2008; 111(6):3220-4. DOI: 10.1182/blood-2007-05-085159. View

Wherry E, Blattman J, Murali-Krishna K, van der Most R, Ahmed R . Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol. 2003; 77(8):4911-27. PMC: 152117. DOI: 10.1128/jvi.77.8.4911-4927.2003. View

Flynn J, Chan J . Immunology of tuberculosis. Annu Rev Immunol. 2001; 19:93-129. DOI: 10.1146/annurev.immunol.19.1.93. View

Dong H, Strome S, Salomao D, Tamura H, Hirano F, Flies D . Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002; 8(8):793-800. DOI: 10.1038/nm730. View

Rodriguez-Manzanet R, Sanjuan M, Wu H, Quintana F, Xiao S, Anderson A . T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice. Proc Natl Acad Sci U S A. 2010; 107(19):8706-11. PMC: 2889349. DOI: 10.1073/pnas.0910359107. View

Jayaraman P, Sada-Ovalle I, Beladi S, Anderson A, Dardalhon V, Hotta C . Tim3 binding to galectin-9 stimulates antimicrobial immunity. J Exp Med. 2010; 207(11):2343-54. PMC: 2964580. DOI: 10.1084/jem.20100687. View

10.

Monney L, Sabatos C, Gaglia J, Ryu A, Waldner H, Chernova T . Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002; 415(6871):536-41. DOI: 10.1038/415536a. View

11.

Sakuishi K, Apetoh L, Sullivan J, Blazar B, Kuchroo V, Anderson A . 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. PMC: 2947065. DOI: 10.1084/jem.20100643. View

12.

Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng X, Sabatos C . Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol. 2003; 4(11):1093-101. DOI: 10.1038/ni987. View

13.

Ju Y, Hou N, Zhang X, Zhao D, Liu Y, Wang J . 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. PMC: 4002548. DOI: 10.1038/cmi.2009.5. View

14.

Ngiow S, Von Scheidt B, Akiba H, Yagita H, Teng M, Smyth M . Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors. Cancer Res. 2011; 71(10):3540-51. DOI: 10.1158/0008-5472.CAN-11-0096. View

15.

Blackburn S, Shin H, Nicholas Haining W, Zou T, Workman C, Polley A . Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2008; 10(1):29-37. PMC: 2605166. DOI: 10.1038/ni.1679. View

16.

Sabatos C, Chakravarti S, Cha E, Schubart A, Sanchez-Fueyo A, Zheng X . 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. DOI: 10.1038/ni988. View

17.

Zhou Q, Munger M, Veenstra R, Weigel B, Hirashima M, Munn D . Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 2011; 117(17):4501-10. PMC: 3099570. DOI: 10.1182/blood-2010-10-310425. View

18.

Koguchi K, Anderson D, Yang L, OConnor K, Kuchroo V, Hafler D . Dysregulated T cell expression of TIM3 in multiple sclerosis. J Exp Med. 2006; 203(6):1413-8. PMC: 2118310. DOI: 10.1084/jem.20060210. View

19.

Fourcade J, Kudela P, Sun Z, Shen H, Land S, Lenzner D . PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J Immunol. 2009; 182(9):5240-9. PMC: 3426222. DOI: 10.4049/jimmunol.0803245. View

20.

Klenerman P, Hill A . T cells and viral persistence: lessons from diverse infections. Nat Immunol. 2005; 6(9):873-9. DOI: 10.1038/ni1241. View