The recently discovered TIM (T cell Immunoglobulin and Mucin domain) gene family has emerged as an important player in immune regulation. We identified TIM-3 as a molecule expressed specifically on CD4+ Th1 and more recently we have found that TIM-3 is also expressed on pathogenic pro-inflammatory Th17 cells. Blockade of the TIM-3 pathway by in vivo administration of soluble TIM-3-lg induced hyper-proliferation of Th1 cells, abrogated tolerance induction and enhanced autoimmunity. Using TIMS.Ig we identified galectin-9 as a TIM-3 ligand which triggers cell death in Th1 cells, thereby dampening Th1 immunity. However, the intracellular pathway(s) that mediate cell death triggered by the TIM-3:galectin-9 interaction in T cells are not known. Using a yeast two hybrid system to identify molecules that bind to the TIM-3 tail in Th1 cells, we pulled down BAT-3 as a molecule that interacts with the cytoplasmic tail of TIM-3. BAT-3 has been shown to be a molecule that regulates survival/cell death during development, suggesting that BAT-3 may be a key molecule that regulates cell death mediated by the TIM-3:galectin-9 interaction in T cells. Although galectin-9 expression is induced by IFN-y on tissue specific antigen presenting cells (APCs), CD4+, CD25+, Fox-P3+ regulatory T cells constitutively express high levels of gaelctin-9. This raises the issue of whether galectin-9 is responsible for some of the inhibitory effects ascribed to regulatory T cells. Preliminary data support this hypothesis in that CD4+.CD25+ regulatory T cells obtained from galectin-9 transgenic mice are more suppressive than T-reg cells obtained from wild type mice. In addition, we have now generated TIM-3 transgenic mice in which T cells constitutively express TIM-3 on the surface. Besides having defects in generating Th1 and Th17 responses, surprisingly the antigen presenting cells from TIM-3 transgenic mice inhibit T cell responses. This suggests that expression of TIM-3 on T cells is in someway responsible for generating """"""""suppressive"""""""" macrophages. Based on these data we have proposed an over-reaching hypothesis that the TIM-3:TIM-3L pathway may have evolved to regulate pro-inflammatory T cell responses at multiple levels including T cells, antigen presenting cells and CD4+.CD25+ regulatory T cells. To address this hypothesis we propose to : 1) Analyze the inhibitory function of TIM-3 on T cells and its role in inducing inhibitory antigen presenting cells in TIM-3 transgenic mice;2) Analyze the signal transduction pathways activated by the galectin-9:TIM-3 interaction and the role of BAT-3 in regulating cell death in T cells and 3) Determine the role of TIM-3L (galectin-9) in the inhibitory function of CD4+.CD25+ regulatory T cells. The studies proposed here will analyze the molecular mechanisms by which TIM-3 mediates its inhibitory function in T cells, antigen presenting cells and regulatory T cells both at the cellular and molecular levels thereby providing possible avenues by which this pathway can be harnessed for regulating immunity and autoimmunity.
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