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Project Summary/Abstract The cell surface receptor T-cell immunoglobulin mucin receptor 4 (Tim-4) has recently been identified as an inhibitory receptor for the monoclonal antibodies (mAbs) directed against a T cell immunoglobulin and mucin-domain (TIM)-3, a transmembrane protein that recognizes a non-polymorphic determinant of HLA class I molecules. Although TIM-3+ T cells play a role in the suppression of autoimmune disease and tumor rejection, anti-TIM-3 mAb has also been shown to abrogate T cell responses to viral and tumour antigens, suggesting TIM-3+ T cells may have an important role in maintaining peripheral tolerance. However, a clear understanding of the mechanism by which TIM-3+ T cells suppress T cell responses in the context of transplantation and cancer is lacking. Preliminary data suggest that TIM-3+ T cells develop from a distinct precursor, the regulatory CD4- 8- double negative (DN) 2 cell. Using a novel mouse model, we have found that TIM-3+ T cell development occurs in a stage-specific manner, with evidence of stable expansion of memory TIM-3+ T cells and effector TIM-3+ T cell differentiation after antigenic activation. Based on these observations, we hypothesize that TIM-3+ T cell development and function are mediated through receptor-ligand interactions. Using specific TIM-3 blocking reagents, we will test our hypothesis by addressing three specific aims: 1) To determine the effect of TIM-3 blockade on the development and function of TIM-3+ T cells in vitro 2) To determine the effect of TIM-3 blockade on Tim-3+ T cell development and function in vivo and 3) To determine the effect of TIM-3 blockade on the development and function of TIM-3+ T cells in a model of cancer. The goal of the proposed research is to enhance our understanding of the mechanism by which Tim-3+ T cell homeostasis is achieved, and to determine whether TIM-3+ T cells have a role in the control of transplantation tolerance and tolerance to cancer. Given that Tim-3+ T cells are a prominent subset of T cells that is enriched in tissues of patients with autoimmune disease or cancer, and that anti- Tim-3 mAb is currently being tested in human cancer immunotherapy trials, the successful outcome of this study will open new avenues to identify and manipulate the human counterpart System Requirements: PC Minimum: OS: Windows 10 64-bit Processor: Intel® Core™ i5-2500K 3.30 GHz Memory: 8 GB RAM Graphics: NVIDIA GeForce GTX 660 2GB/AMD Radeon HD 7870 2GB DirectX: Version 11 Storage: 25 GB available space Network: Broadband Internet connection Mac Minimum: OS: OS X Yosemite 10.10.5 64-bit
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