Tim3 and Mycobacterium tuberculosis

描述（由申请人提供）：对微生物病原体的免疫涉及由多种途径调节的许多检查和平衡。这一应用解决了Tim3 （T细胞免疫球蛋白和粘蛋白结构域家族的一员）在抵抗结核病中所起的新的和潜在的关键作用。Tim3正在成为适应性免疫和先天免疫的重要调节因子，并且在人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得到研究。虽然通过TH1细胞上的Tim3信号传导被认为可以传递负面信号，从而减少非预期的组织炎症，但Tim3与其配体结合在参与抗原呈递细胞上的后果尚不清楚。我们已经发现Tim3与其配体半乳糖凝集素-9 （Gal9）结合可以在体内和体外刺激先天细胞的抗菌活性。Mtb感染的巨噬细胞表达的Gal9的Tim3参与诱导caspase-1依赖性IL-12分泌并限制细胞内细菌复制。我们还发现，表达tim3的CD4+和CD8+ T细胞在感染致病性结核分枝杆菌（Mtb）的小鼠肺部积聚。如果，正如在慢性病毒感染的人类T细胞中所报道的那样，Tim3信号传导导致T细胞功能障碍和凋亡，我们假设肺中Tim3+ T细胞与表达Gal9的巨噬细胞之间的相互作用导致T细胞衰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反应的双向调节回路的核心参与者。在急性感染的情况下，这个回路可能是一个重要的机制，它限制了过度旺盛的免疫反应造成的组织损伤和免疫病理，同时激活了针对微生物病原体的先天免疫。另一方面，这种机制在慢性感染中可能是有害的，并且由于克隆性过早收缩或T细胞衰竭而导致免疫不理想。这些研究的意义超出了提供对结核病免疫的更好理解。我们的数据为适应性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，下面提出的研究将解决一个潜在的关键，但尚未得到充分重视的免疫途径，它影响对结核病和其他病原体的免疫力。我们的目标是：Tim3/Gal9如何激活MX，刺激先天免疫，导致细胞内Mtb的杀伤？7 .目标IL-1及其下游介质是否激活人MX杀死结核分枝杆菌？7 .目标Tim3/Gal9相互作用如何在体内调节对结核病的免疫？

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?