The Role of Group 3 Innate Lymphoid cells (ILC3) in Tuberculosis

项目摘要/摘要 世界上大约三分之一的人口潜伏感染结核病(LTBI)，寿命为10% 发展为临床肺结核(PTB)的风险。全球抗击结核病的努力因出现结核病而受阻 结核分枝杆菌耐药株(Mtb)和目前获得许可的可变疗效 卡介苗(BCG)。肺部感染结核分枝杆菌后，雾化细菌被吸入并相互作用。 与宿主结合，导致免疫细胞向肺内募集，形成结节肉芽肿。虽然 肉芽肿的存在一直被认为是结核病的标志，两者在免疫学上的差异 保护性肉芽肿和非保护性肉芽肿一直难以捉摸。我们最近公布的数据表明， 肉芽肿内可诱导的支气管炎相关淋巴组织(IBALT)的存在是指示性的 介导结核分枝杆菌控制的保护性肉芽肿。相比之下，浸润性中性粒细胞的特征是 肺结核患者的肉芽肿性炎症。这些新发现极大地改变了总体共识 结核病肉芽肿通常是保护性的，但相反地提出了新的范例，在结核病期间，保护性 肉芽肿含有iBALT，而非保护性肉芽肿是中性粒细胞。我们新的初步数据 证明第三组先天淋巴样细胞(ILC3)是第一批迅速积累的先天细胞 在结核分枝杆菌感染时，肺组织中有大量的结核分枝杆菌感染，并定位于含有iBALT的肉芽肿的B细胞滤泡内。ILC3 小鼠的缺乏也会导致早期结核分枝杆菌易感性的增加，并与巨噬细胞减少相吻合。 积聚和形成不良的iBALT结构。因此，这项拨款中提议的工作将机械性地 解决ILC3在结核分枝杆菌感染中的功能先天作用。在具体目标1中，我们将定义主机因素 介导结核分枝杆菌感染后早期肺内ILC3蓄积。在具体目标2中，我们将确定 ILC3介导含有iBALT的肉芽肿形成并促进结核分枝杆菌控制的机制(S)。在……里面 具体目标3，我们将确定ILC3在疫苗诱导的结核病免疫中的作用，并确定新的 靶向ILC3以提高对结核分枝杆菌感染的免疫力的方法。这些目标加在一起将提供新的 ILC3在介导iBALT形成和诱导保护性宿主免疫方面发挥关键作用的证据。 识别以ILC3细胞为靶点以提高疫苗免疫力的新方法，如这里提出的，将打开新的 可用于结核病疫苗设计的途径。

PROJECT SUMMARY/ABSTRACT Approximately one-third of the world's population is latently infected with TB (LTBI) and have a 10% lifetime risk of developing clinical pulmonary TB (PTB). Global efforts to combat TB are hampered by the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), and variable efficacy of the currently licensed vaccine, M.bovis BCG (BCG). After pulmonary infection with Mtb, aerosolized bacteria are inhaled and interact with the host, resulting in the recruitment of immune cells to the lung to form the tubercle granuloma. Although the presence of granuloma has long been considered a hallmark of TB, the immunological differences between a protective granuloma and a non-protective granuloma has been elusive. Our recent published data, suggest that the presence of inducible Bronchus Associated Lymphoid Tissue (iBALT) within granulomas is indicative of protective granulomas that mediate Mtb control. In contrast, infiltrating neutrophils are characteristic of granulomatous inflammation in PTB patients. These new findings significantly change the overall consensus that TB granulomas in general are protective, but instead put forth the new paradigm that during TB, protective granulomas contain iBALT, while non-protective granulomas are neutrophilic. Our new preliminary data demonstrate that Group 3 Innate Lymphoid cells (ILC3) are among the first innate cells to rapidly accumulate in the lungs upon Mtb infection, and localize within B cell follicles in iBALT-containing granulomas. ILC3 deficiency in mice also results in increased early Mtb susceptibility, and coincides with reduced macrophage accumulation and poorly formed iBALT structures. Thus, the work proposed in this grant will mechanistically address a functional innate role for ILC3 in Mtb infection. In Specific Aim 1 we will define the host factors that mediate early lung ILC3 accumulation following Mtb infection. In Specific Aim 2, we will determine the mechanism(s) via which ILC3 mediate formation of iBALT-containing granulomas and facilitate Mtb control. In Specific Aim 3, we will determine a role for ILC3 in vaccine-induced immunity against TB, and identify new ways to target ILC3 to improve immunity against Mtb infection. Together these aims will provide novel evidence for a critical role for ILC3 in mediating iBALT formation and inducing protective host immunity to TB. Identifying new ways to target ILC3 cells to improve vaccine-immunity as proposed here, will open up novel avenues that can be harnessed for TB vaccine design.