CRTAM在快速性抗结核免疫应答和杀菌性免疫保护过程中的作用及机制

目前宿主抗结核杆菌(Mtb)感染的有效保护性免疫应答尚未阐明。结核感染抗性人群是与结核病(TB)患者密切接触但无感染特征的群体，能快速清除感染的Mtb，是探究有效保护性免疫的最适人群。预实验发现CRTAM在结核感染抗性人群外周血向肺部迁移的效应细胞中高表达，CRTAM+CD107a+CD3+细胞可有效杀灭巨噬细胞内Mtb。据此推测CRTAM在宿主快速清除结核感染过程中发挥重要作用。本研究拟阐明结核抗原反应性CRTAM+CD107a+CD3+细胞在结核感染抗性人群中的特异表型及功能特征，证实CRTAM与固有免疫类T细胞发挥快速性效应功能相关；通过功能性单细胞测序等技术阐明CRTAM+CD107a+CD3+抗结核感染机制；利用基因敲除小鼠等证实CRTAM及CRTAM-Necl2信号轴在抗结核感染中的作用；阐明CRTAM在TB体内功能受损的机制。本研究有助于揭示宿主抗结核有效保护性免疫新机制。

The occurrence and development of tuberculosis (TB) are determined by effective protective immunity in humans after Mycobacteria tuberculosis (Mtb) infection. However, it is unclear what is the protective immune response to Mtb infection? Resisters are special human subjects who repeatedly expose to sputum Mtb positive TB patients but remain uninfected, might rapidly clear Mtb in early stage infection. So, Resisters are the best human subjects used to explore the protective immune response to Mtb infection. In the previous studies, we have found that CRTAM highly expressed in effector cells expressing chemokine markers in blood of Resisters after PPD inoculation. The CRTAM+CD107a+CD3+ T cells isolated from blood of Resisters with induction of Mtb antigen could effectively inhibit Mtb growth in macrophages. So, we hypothesized that the CRTAM and its related signal pathway play important roles in rapid clearance of Mtb infection in early stage in humans. To test this hypothesis and elucidate immune mechanisms, we will conduct the following interrelated studies: Characterizing the specific phenotypes and functions of CRTAM+CD107a+CD3+ cells in Resisters by comparing with other subjects including TB patients, latent tuberculosis infected subjects and healthy controls; Verifying the correlation between CRTAM expression and the rapid response function of innate-like T cells in Resisters; Exploring the mechanisms of CTRAM+CD107a+CD3+ cells against Mtb infection by functional single cell sequencing and other methods; Determining that CRTAM and the CRTAM-Necl2 signal axis play protective roles in immune response against Mtb infection using the CRTAM or Necl2 knock-out mice comparing to wild type mice; And clarifying the dysfunction of CRTAM in TB patients. Findings will prove that CRTAM related signal pathway may contribute to the mechanism for sterilizing immunity against TB, and provide new concepts and protective mechanisms of anti-TB immune response.