Tim3 and Mycobacterium tuberculosis

描述(由申请人提供)：对微生物病原体的免疫涉及许多由多个途径调节的制衡。TIM3是T细胞免疫球蛋白和粘蛋白结构域蛋白质家族中的一员，它在预防结核病中发挥着新的和潜在的关键作用。TIM3是一种重要的适应性免疫和先天免疫调节因子，在人类和小鼠之间是保守的。然而，TIM3在调节对细菌病原体的免疫中的作用尚未被研究。虽然通过TIM3在TH1细胞上传递信号据称可以传递负面信号，从而可能减少意外的组织炎症，但TIM3与其配体结合对参与抗原提呈细胞的后果尚不清楚。我们发现TIM3与其配体Galectin-9(Gal9)结合，在体内和体外都能刺激天然细胞的抗菌活性。结核分枝杆菌感染的巨噬细胞表达的Gal9与TIM3结合可诱导caspase-1依赖的IL-12分泌，抑制细菌在细胞内的复制。我们还发现，表达TIM3的CD4和CD8T细胞在感染强毒结核分枝杆菌(Mtb)的小鼠肺中积聚。如果在慢性病毒感染过程中，TIM3信号导致T细胞功能障碍和细胞凋亡，我们假设肺中的TIM3T细胞和表达Gal9的巨噬细胞之间的相互作用导致T细胞耗竭，并损害抗分枝杆菌免疫。因此，TIM3和Gal9似乎是调节抗微生物TH1反应的双向调节电路的中心角色。在急性感染的情况下，这一回路可能是一种重要的机制，它可以限制组织损伤和过度活跃的免疫反应的免疫病理学，同时激活对微生物病原体的天然免疫。另一方面，这种机制在慢性感染过程中可能是有害的，并由于过早的克隆性收缩或T细胞耗尽而导致次优免疫。这些研究不仅提供了对结核病免疫力的更好的了解，还具有其他意义。我们的数据为适应性免疫系统和先天免疫系统之间的串扰如何发生建立了一个新的范例。因此，下面建议的研究将解决一个潜在的关键但尚未得到充分认识的免疫途径，它影响对结核病的免疫力，也可能影响其他病原体。我们的目标是：7目标1.TIM3/Gal9如何激活MX，刺激天然免疫，并导致细胞内结核分枝杆菌的杀伤？7目标2.IL-1及其下游介质是否激活人MX以杀死结核分枝杆菌？7目标3.TIM3/Gal9相互作用如何调节体内对结核杆菌的免疫？

DESCRIPTION (provided by applicant): Immunity to microbial pathogens involves numerous checks and balances that are regulated by multiple pathways. This application addresses the novel and potentially critical role that Tim3, a member of the T cell Immunoglobulin and Mucin domain family of proteins, plays in the defense against tuberculosis. Tim3 is emerging as an important regulator of both adaptive and innate immunity, and is conserved between humans and mice. However, the role of Tim3 in modulating immunity to bacterial pathogens has not been examined. While signaling via Tim3 on TH1 cells has been purported to deliver a negative signal that could reduce unintended tissue inflammation, the consequence of Tim3 binding to its ligand on participating antigen-presenting cells is unclear. We have discovered that Tim3 binding to its ligand, Galectin-9 (Gal9) stimulates antibactericidal activity in innate cells both in vivo and in vitro. Tim3 engagement of Gal9 expressed by Mtb infected macrophages induces caspase-1 dependent IL-12 secretion and restricts intracellular bacterial replication. We also find that Tim3-expressing CD4+ and CD8+ T cells accumulate in the lungs of mice infected with virulent M. tuberculosis (Mtb). If, as has been reported for human T cells during chronic viral infection, Tim3-signaling leads to T cell dysfunction and apoptosis, we hypothesize that interactions between Tim3+ T cells in the lung and Gal9 expressing macrophages leads to T cell exhaustion and impairs anti-mycobacterial immunity. Thus, it appears that Tim3 and Gal9 are central players in a bidirectional regulatory circuit that modulates antimicrobial TH1 responses. In the case of acute infection, this circuit could be an important mechanism that limits tissue damage and immunopathology from an overly exuberant immune response, while simultaneously activating innate immunity against microbial pathogens. On the other hand, such a mechanism may be detrimental during chronic infection and lead to suboptimal immunity because of premature clonal contraction or T cell exhaustion. These studies have implications beyond providing a better understanding of immunity to tuberculosis. Our data establish a novel paradigm for how cross-talk between the adaptive and innate immune system occurs. Therefore, the studies proposed below will address a potentially critical, but as yet underappreciated immunological pathway, that affects immunity to tuberculosis and possibility other pathogens as well. Our aims are: 7 Aim 1. How does Tim3/Gal9 activate MX, stimulate innate immunity, and lead to killing of intracellular Mtb? 7 Aim 2. Does IL-1 and its downstream mediators activate human MX to kill Mtb? 7 Aim 3. How does the Tim3/Gal9 interaction modulate immunity to tuberculosis in vivo?