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Th 1/Tc 1细胞上差异表达的分子，并且最近发现Tim-3也在致病性促炎性Th 17细胞上表达。我们鉴定了半乳糖凝集素-9作为Tim-3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的Th 1/Tc 1应答终止。这些研究，连同其他体内阻断可溶性Tim- 3的研究表明，Tim-3是抑制效应Th 1/Tc 1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细胞耗竭。在慢性病毒感染（例如HIV）和癌症中效应T细胞上Tim-3表达增加，使它们功能失调，然而在人自身免疫疾病中，效应T细胞上Tim-3表达丧失，使它们高度促炎和致病。因此，Tim-3在多种人类疾病中起着重要作用，但令人惊讶的是，对Tim-3的功能生物学知之甚少：尚不清楚是什么诱导T细胞上的Ti-3表达以及它如何介导其抑制作用。为了了解细胞内 为了研究介导Tim-3功能的途径，我们进行了酵母双杂交筛选，并将Bat 3（HLA-B相关转录物3）鉴定为与Tim-3胞质尾区结合的分子。当与Tim-3尾部结合时，Bat 3充当调节Tim-3抑制功能的分子“看门人”。为了解决这一假设，我们提出了以下具体目标：1）识别 Tim-3通过其向T细胞发出信号以诱导T细胞功能障碍/衰竭的分子机制。由于我们已经确定了Bat 3作为Tim-3尾的结合伴侣，我们将分析Bat-3的条件性丧失是否会诱导T细胞功能障碍，并研究Bat 3如何与Tim-3结合调节近端CD 3-TcR信号传导。拟议的研究将确定Tim-3介导其在T细胞中的抑制功能的分子机制，该功能可用于调节自身免疫反应。虽然增强Tim-3信号可以抑制自身免疫性疾病，但抑制Tim-3功能可以增强慢性病毒感染（如HIV）和癌症的免疫反应。

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.