The Molecular Mechanism of Tim-3-mediated T Cell Dysfunction

描述（由申请人提供）：我们克隆了Tim-3作为在产生ifn - γ的Th1/Tc1细胞上差异表达的分子，最近发现Tim-3也在致病性促炎Th17细胞上表达。我们确定了半乳糖凝集素-9是Tim-3的配体，并发现半乳糖凝集素-9与Tim-3的相互作用导致细胞死亡和随后Th1/Tc1反应的终止。这些研究，连同其他可溶性Tim-3的体内阻断研究，表明Tim-3是抑制效应体Th1/Tc1免疫所必需的抑制分子。令人兴奋的新数据表明，Tim-3也参与诱导T细胞衰竭。在慢性病毒感染（如HIV）和癌症中，效应T细胞上的Tim-3表达增加，使其功能失调，然而在人类自身免疫性疾病中，效应T细胞上的Tim-3表达缺失，使其具有高度促炎和致病性。因此，Tim-3在多种人类疾病中发挥着重要作用，但令人惊讶的是，人们对Tim-3的功能生物学知之甚少：不清楚是什么诱导了T细胞上的Ti-3表达，以及它如何介导其抑制作用。来了解细胞内

DESCRIPTION (provided by applicant): 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.