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Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease


Activation of naive CD4+ T-helper cells results in the development of at least two distinct effector populations, Th1 and Th2 cells1,2,3. Th1 cells produce cytokines (interferon (IFN)-γ, interleukin (IL)-2, tumour-necrosis factor (TNF)-α and lymphotoxin) that are commonly associated with cell-mediated immune responses against intracellular pathogens, delayed-type hypersensitivity reactions4, and induction of organ-specific autoimmune diseases5. Th2 cells produce cytokines (IL-4, IL-10 and IL-13) that are crucial for control of extracellular helminthic infections and promote atopic and allergic diseases4. Although much is known about the functions of these two subsets of T-helper cells, there are few known surface molecules that distinguish between them6. We report here the identification and characterization of a transmembrane protein, Tim-3, which contains an immunoglobulin and a mucin-like domain and is expressed on differentiated Th1 cells. In vivo administration of antibody to Tim-3 enhances the clinical and pathological severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease, and increases the number and activation level of macrophages. Tim-3 may have an important role in the induction of autoimmune diseases by regulating macrophage activation and/or function.

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Figure 1: Cloning of a Th1-specific cell surface protein, Tim-3.
Figure 2: Tim-3 is detected on the surface of Th1 DO11.10 T cells after the third round of stimulation.
Figure 3: Tim-3 is expressed on CD4+ and CD8+ T cells during the course of EAE.
Figure 4: Treatment with anti-Tim-3 antibody enhances EAE.
Figure 5: Treatment with anti-Tim-3 antibody induces macrophage activation.


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We thank L. Nicholson, N. Ruggli, L. Glimcher and H. Cantor for comments on this manuscript; R. Nazareno and E. Howard for technical help and D. Schlesinger for discussions. This work was supported by grants from the National Multiple Sclerosis Society, New York, the Swiss National Science Foundation, and the National Institutes of Health (M.D.).

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Correspondence to Vijay K. Kuchroo.

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

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