In this PPG, a multidisciplinary group has been established to analyze the function of a new family of genes that we discovered called TIM (T cell, Immunoglobulin, and Mucin domain containing molecule), specifically focusing on the role of one of its members, TIM-3, in regulating immunity and tolerance in both human diseases and their animal models. We focus on TIM-3 because a series of studies from our PPG group and others demonstrate that TIM-3 plays a critical role in inducing T cell dysfunction/ exhaustion in both chronic viral infections (HIV, HCV, HBV) and cancer (both murine and human) and that there is a defect in TIM-3- mediated regulation in human autoimmune diseases. Accordingly, repressing TIM-3 signals can improve immunity in the setting of chronic viral infection and cancer, while boosting TIM-3 signals can dampen auto- aggressive immune responses in the setting of autoimmunity. However, in order to successfully target Tim-3 therapeutically for the treatment of these diseases, a greater understanding of the molecular mechanisms that govern TIM-3 expression and TIM-3-mediated regulation of T cell responses is required. This PPG brings together three research projects and cores, involving nine talented investigators, to address the regulation of TIM-3 in 3 diseases: multiple sclerosis, cancer, and TB. The proposed studies will utilize and examine animal models and human disease conditions. The three projects are highly integrated and address a common theme: What is the mechanism by which TIM-3 expression and function is dysregulated in various disease states and how can its function be modulated? The main themes of the three projects are: 1. Role of TIM-3 in T cell dysfunction in cancer (Project I: Vijay K. Kuchroo, Ana C. Anderson, and Richard Blumberg, PIs); 2. TIM-3 regulation of CNS autoimmune responses (Project II: David A. Hafler and Joan Goverman, PIs); 3. Role of the IL-27/TIM-3 axis in regulating immunity to TB (Project III: Samuel Behar, and Chen Zhu, PIs). The three cores (Administrative, Transcription, Transgenic/Knock-out Mouse) will support these three projects by providing administrative coordination, a common set of standardized tools, and centralized computational data analysis and sharing across projects, thereby accelerating discovery in an efficient and cost effective manner. As the function of Tim-3 varies across the different inflammatory diseases investigated in the individual projects, the projects in the PPG will instruct each other and together will build a comprehensive understanding of the mechanisms that drive TIM-3-mediated regulation of immunity and tolerance, thus providing critical information for how to exploit this pathway for therapeutic purposes in human disease.

Public Health Relevance

TIM-3 has emerged as key molecule that induces T cell dysfunction/exhaustion in effector T cells in chronic human viral infections like HIV and HCV and in cancer. In contrast, there is a defect in TIM-3-mediated regulation in the autoimmune disease multiple sclerosis (MS). This proposal will provide a greater understanding of how TIM-3 is induced and how it functions in effector T cells so that the pathway can be therapeutically exploited in chronic microbial infections, cancer, and autoimmune diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Esch, Thomas R
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Brigham and Women's Hospital
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