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.
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.
|Meyer Zu Horste, Gerd; Przybylski, Dariusz; Schramm, Markus A et al. (2018) Fas Promotes T Helper 17 Cell Differentiation and Inhibits T Helper 1 Cell Development by Binding and Sequestering Transcription Factor STAT1. Immunity 48:556-569.e7|
|Iyer, Shankar S; Gensollen, Thomas; Gandhi, Amit et al. (2018) Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses. Cell 173:1123-1134.e11|
|Chihara, Norio; Madi, Asaf; Kondo, Takaaki et al. (2018) Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 558:454-459|
|Dixon, Karen O; Schorer, Michelle; Nevin, James et al. (2018) Functional Anti-TIGIT Antibodies Regulate Development of Autoimmunity and Antitumor Immunity. J Immunol 200:3000-3007|
|Wu, Chuan; Chen, Zuojia; Xiao, Sheng et al. (2018) SGK1 Governs the Reciprocal Development of Th17 and Regulatory T Cells. Cell Rep 22:653-665|
|Sabatos-Peyton, Catherine A; Nevin, James; Brock, Ansgar et al. (2018) Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have functional efficacy. Oncoimmunology 7:e1385690|
|Carpenter, Stephen M; Yang, Jason D; Lee, Jinhee et al. (2017) Vaccine-elicited memory CD4+ T cell expansion is impaired in the lungs during tuberculosis. PLoS Pathog 13:e1006704|
|Wang, Chao; Singer, Meromit; Anderson, Ana C (2017) Molecular Dissection of CD8+ T-Cell Dysfunction. Trends Immunol 38:567-576|
|Goods, Brittany A; Hernandez, Amanda L; Lowther, Daniel E et al. (2017) Functional differences between PD-1+ and PD-1- CD4+ effector T cells in healthy donors and patients with glioblastoma multiforme. PLoS One 12:e0181538|
|Joller, Nicole; Kuchroo, Vijay K (2017) Tim-3, Lag-3, and TIGIT. Curr Top Microbiol Immunol 410:127-156|
Showing the most recent 10 out of 78 publications