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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Kuchroo, V. K., Umetsu, D. T., DeKruyff, R. H. & Freeman, G. J. The TIM gene family: emerging roles in immunity and disease. Nature Rev. Immunol. 3, 454–462 (2003).
Umetsu, S. E. et al. TIM-1 induces T cell activation and inhibits the development of peripheral tolerance. Nature Immunol. 6, 447–454 (2005).
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).
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).
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).
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).
Degauque, N. et al. Immunostimulatory Tim-1 specific antibody deprograms Tregs and prevents transplant tolerance in mice. J. Clin. Invest. 118, 735–741 (2008).
Xiao, S. et al. Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function. J. Exp. Med. 204, 1691–1702 (2007).
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).
Binne, L., Scott, M. L. & Rennert, P. D. Human TIM-1 associates with the TCR complex and up-regulates T cell activation signals. J. Immunol. 178, 4342–4350 (2007).
Chakravarti, S. et al. TIM-2 regulates T helper type 2 responses and autoimmunity. J. Exp. Med. 202, 437–444 (2005).
Kumanogoh, A. et al. Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature 419, 629–633 (2002).
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).
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).
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).
Rodriguez-Manzanet, R. et al. TIM-4 expressed on APCs induces T cell expansion and survival. J. Immunol. 180, 4706–4713 (2008).
Mizui, M. et al. Bimodal regulation of T cell-mediated immune responses by TIM-4. Int. Immunol. 20, 695–708 (2008).
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).
Zhu, C. et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nature Immunol. 6, 1245–1252 (2005).
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).
Cao, E. et al. T cell immunoglobulin mucin-3 crystal structure reveals a novel ligand binding surface. Immunity 26, 311–321 (2007).
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).
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).
Miyanishi, M. et al. Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435–439 (2007).
Kobayashi, N. et al. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27, 927–940 (2007).
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).
Koguchi, K. et al. Dysregulated T cell expression of TIM3 in multiple sclerosis. J. Exp. Med. 203, 1413–1418 (2006).
Yang, L., Anderson, D. E., Kuchroo, J. & Hafler, D. A. Lack of TIM-3 immunoregulation in multiple sclerosis. J. Immunol. 180, 4409–4414 (2008).
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Kuchroo, V., Dardalhon, V., Xiao, S. et al. New roles for TIM family members in immune regulation. Nat Rev Immunol 8, 577–580 (2008). https://doi.org/10.1038/nri2366
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