Tim3 and Mycobacterium tuberculosis

Tim3 和结核分枝杆菌

• 批准号: 8629422
• 负责人: SAMUEL M BEHAR
• 金额: $ 49.44万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629422
• 关键词: 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one; Abbreviations; Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Antigen-Presenting Cells; Antimicrobial Effect; Apoptosis; Bacteria; Binding; CD8B1 gene; Caspase-1; Cell Line; Cell surface; Cells; Chimeric Proteins; Chronic; Colony-forming units; Data; Dendritic Cells; Disease; Equilibrium; Functional disorder; Galactose Binding Lectin; Growth; Host resistance; Human; Immune; Immune response; Immune system; Immunity; Immunoglobulins; In Vitro; Infection; Inflammation; Interferons; Interleukin-1; Interleukin-1 beta; Interleukin-12; Interleukin-18; Intravenous; Knock-out; Lead; Ligands; Lung; Major Histocompatibility Complex; Mediating; Mediator of activation protein; Molecular; Mucins; Mus; Mycobacterium tuberculosis; Myeloid Cells; Natural Immunity; Nitric Oxide; Nitrogen; Outcome; Oxidases; Oxygen; Pathway interactions; Peritoneal; Phagocytes; Physiological; Play; Production; Protein Family; Pulmonary Tuberculosis; Recruitment Activity; Reporting; Research; Research Proposals; Role; Signal Transduction; Staining method; Stains; T-Lymphocyte; TNF gene; Testing; Tissues; Toll-like receptors; Transgenic Organisms; Tuberculosis; Tumor Necrosis Factor-alpha; Virulent; Virus Diseases; adaptive immunity; antimicrobial; bactericide; cytokine; design; exhaustion; functional status; global health; human NOS2A protein; immunopathology; in vivo; in vivo Model; killings; lymph nodes; macrophage; member; microbial; mycobacterial; novel; pathogen; premature; public health relevance; research study; response; tuberculosis immunity; tuberculosis treatment

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?

描述（由申请人提供）：对微生物病原体的免疫力涉及多种由多个途径调节的检查和平衡。该应用解决了Tim3（T Tim3）的新颖和潜在的至关重要的作用，即T细胞免疫球蛋白和粘蛋白结构域的蛋白质家族在防御结核病的防御中起着。 TIM3成为适应性和先天免疫的重要调节剂，并且是人类和小鼠之间的保守。但是，尚未检查TIM3在调节细菌病原体免疫力中的作用。虽然据称通过TIM3信号传导TH1细胞上的信号传递可能会减少意外组织炎症的负信号，但TIM3与其配体与参与抗原抗原的细胞结合的后果尚不清楚。我们发现TIM3与其配体的Galectin-9（GAL9）结合刺激了体内和体外的先天细胞中的抗菌活性。 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细胞在感染结核分枝杆菌（MTB）的小鼠的肺中积累。如果在慢性病毒感染期间人类T细胞的报道称，TIM3信号会导致T细胞功能障碍和凋亡，我们假设肺和GAL9表达巨噬细胞的Tim3+ T细胞之间的相互作用会导致T细胞衰竭并损害抗肌酸免疫。因此，TIM3和GAL9似乎是调节抗微生物Th1反应的双向调节电路中的中心参与者。在急性感染的情况下，该电路可能是一种重要的机制，该机制限制了组织损伤和免疫病理学，同时激活对微生物病原体的先天免疫力。另一方面，这种机制在慢性感染过程中可能有害，并且由于过早的克隆收缩或T细胞衰竭而导致次优免疫。这些研究具有对结核病免疫的更好理解的意义。我们的数据为适应性和先天免疫系统之间的串扰如何建立了一种新颖的范式。因此，下面提出的研究将解决潜在的至关重要的，但尚未被低估的免疫学途径影响对结核病的免疫和其他病原体的免疫。我们的目标是：7 AIM 1。TIM3/GAL9如何激活MX，刺激先天免疫力并导致杀死细胞内MTB？ 7 AIM 2。IL-1及其下游介体是否激活了人类MX以杀死MTB？ 7目标3。tim3/gal9相互作用如何调节体内结核病的免疫力？