We cloned Tim-3 as a molecule differentially expressed on IFN-gamma producing Th1/Tc1 cells and more recently found that Tim-3 is also expressed on pathogenic pro-inflammatory Th17 cells. We identified Galectin-9 as the Tim-3 ligand, and found that the interaction of galectin-9 with Tim-3 led to cell death and subsequent termination of Th1/Tc1 responses. These studies, together with other in vivo blockade studies with soluble Tim- 3, suggested that Tim-3 is inhibitory molecule necessary for dampening of effector Th1/Tc1 immunity. Exciting new data suggests that Tim-3 is also involved in inducing T cell exhaustion. Tim-3 expression is increased on effector T cells in chronic viral infections (e.g HIV) and cancers, rendering them dysfunctional, however in human autoimmune diseases there is loss of Tim-3 expression on effector T cells making them highly proinflammatory and pathogenic. Therefore, Tim-3 plays an important role in multiple human diseases, yet surprisingly little is known about the functional biology of Tim-3: it is not clear what induces Ti-3 expression on T cells and how it mediates its inhibitory effects. To understand the intracellular pathways that mediate Tim-3 function, we undertook a yeast two-hybrid screen and identified Bat3 (HLA-B associated transcript 3) as a molecule that binds to the Tim-3 cytoplasmic tail. Bat3, when bound to the Tim-3 tail, acts as a molecular """"""""gate-keeper"""""""" that regulates Tim-3 inhibitory functions. To address this hypothesis we propose the following specific aim: 1) Identify molecular mechanisms by which Tim-3 signals into T cells to induce T cell dysfunction/exhaustion. Since we have identified Bat3 as a binding partner for the Tim-3 tail, we will analyze whether conditional loss of Bat-3 will induce T cell dysfunction and study how Bat3 bound to Tim-3 regulates proximal CD3-TcR signaling. The proposed studies will identify the molecular mechanisms by which Tim-3 mediates its inhibitory function in T cells that could be exploited to regulate autoimmune responses. While boosting Tim-3 signals could dampen autoimmune disease, repressing Tim-3 function could augment immune responses in chronic viral infections (e.g. HIV) and cancer.

Public Health Relevance

Tim-3 has emerged as an important player in inducing T cell dysfunction in chronic human viral infections like HIV and HCV. In contrast, in a number of human autoimmune diseases, such as multiple sclerosis, psoriasis, rheumatoid arthritis, and type 1 diabetes, there is evidence that Tim-3 is functioning suboptimally, resulting in the generation of highly pathogenic T cells. This proposal will provide a greater understanding of how Tim-3 functions in T cells in order that the Tim-3 pathway can be therapeutically exploited in chronic viral infections, cancers, and autoimmune diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Prograis, Lawrence J
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Brigham and Women's Hospital
United States
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