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.
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.
