阐明结核的免疫调控机制是开发新的结核疫苗、诊断及治疗技术从而遏制结核严峻疫情的关键基础。我们（PNAS，2015）最近证明结核感染诱导CD244在CD8+ T效应细胞中显著上调表达并抑制CD8+ T细胞的效应功能。但是，我们的前期工作及同行也证明T细胞效应功能对控制结核感染的结局具有保护性或病理性双重影响，所以CD244介导的CD8+ T细胞免疫抑制究竟如何决定结核感染的结局仍不清楚。为此，项目拟在前期工作及预实验基础上，继续在结核及耐药结核感染的小鼠中，去或不去除CD4+ T细胞并阻断CD244，或者阻断CD8+ T细胞的CD244并将其过继转移至结核感染的小鼠，从而系统阐述CD244是否并如何影响小鼠的免疫功能、结核负担与病理病变；同时，将分析CD244的表达与结核病情发展与转归的临床相关性。项目将率先准确定义CD244的免疫保护或病理功能及其机制，从而为结核的防治提供新技术、新思路。

Elucidation of immune regulation mechanisms in tuberculosis (TB) infection is one of fundamental works to develop novel TB vaccines, diagnostic and therapeutic technologies. We (PNAS, 2015) have recently demonstrated that active TB infection in humans induced up-regulation of CD244 on CD8+T effectors, which significantly inhibited the effector functions of CD8+T effectors. However, since the T cell effector functions may mediate either protective immunity or detrimental immunopathology in TB, it remains unclear whether and how CD244-inhibited effector functions of CD8+T cells may determine the TB infection outcomes. Thus, we will continuously develop following strategies to address the exact role of CD244 signaling in determining the TB infection outcomes: (i) Mice will be first infected with TB and drug-resistant TB, and used anti-CD244 mAb to block the CD244 signaling in presence or absence of CD4+T cells deletion; (ii) CD8+T effectors will be treated with anti-CD244 blockade Ab to block the CD244 signaling in CD8+T cells, and then these CD8+T cells with or without CD244 blockade will be adoptive transferred to TB-infected mice. We will then fully evaluate the TB bacillus burdens and TB pathology as well as immunological responses of T cells in mice. We will also analyze the correlation between CD244 expression on CD8+T cells and development, progress, and prognosis of human TB infection. The current project will provide the first line of evidence demonstrating the exact role of CD244 signaling in determining TB infection outcomes, and therefore will serve as critical basis for development of CD244-based novel TB prevention and treatment methods.