Tim3 and Mycobacterium tuberculosis

描述（由申请方提供）：对微生物病原体的免疫力涉及由多种途径调节的众多制衡。本申请解决了T细胞免疫球蛋白和粘蛋白结构域蛋白家族的成员Tim 3在防御结核病中发挥的新的和潜在的关键作用。Tim 3正在成为适应性免疫和先天免疫的重要调节因子，并且在人类和小鼠之间是保守的。然而，尚未研究Tim 3在调节对细菌病原体的免疫中的作用。虽然在TH 1细胞上通过Tim 3的信号传导被认为传递了可以减少非预期组织炎症的负信号，但Tim 3与其配体结合在参与抗原呈递细胞上的结果尚不清楚。我们已经发现Tim 3与其配体半乳糖凝集素-9（Gal 9）结合在体内和体外刺激先天细胞中的抗杀菌活性。由Mtb感染的巨噬细胞表达的Gal 9的Tim 3接合诱导半胱天冬酶-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Tim 3的CD 4+和CD 8 + T细胞在感染强毒M.结核病（Mtb）。如果，如已经报道的慢性病毒感染期间的人T细胞，Tim 3信号传导导致T细胞功能障碍和细胞凋亡，我们假设肺中的Tim 3 + T细胞与表达Gal 9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，似乎Tim 3和Gal 9是调节抗微生物TH 1应答的双向调节回路中的核心参与者。在急性感染的情况下，这种回路可能是一种重要的机制，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学，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期间可能是有害的，并且由于过早的克隆收缩或T细胞耗竭而导致次优免疫。这些研究的意义不仅仅在于更好地了解结核病的免疫力。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式。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，影响免疫结核病和其他病原体的可能性。我们的目标是：7目标1。Tim 3/Gal 9如何激活MX，刺激先天免疫，并导致细胞内Mtb的杀伤？7目标2. IL-1及其下游介质激活人MX杀死Mtb吗？3. Tim 3/Gal 9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?