T细胞抗原特异性免疫应答的调控机制

T细胞对炎症反应特别是慢性炎症反应起着重要的调控功能。T细胞能特异性地识别抗原并产生特异性的免疫应答。T细胞抗原受体（TCR）对T细胞的功能发挥起着关键作用。抗原与TCR的结合能引起TCR的酪氨酸磷酸化，由此开启下游信号通路并活化T细胞。不同的抗原可以通过TCR信号通路引发不同的免疫应答。我们的前期工作发现了TCR维持静息态的机制（Cell 2008，第一作者）以及TCR活化信号放大的机制（Nature 2013，通讯作者），但仍未阐明抗原如何通过TCR磷酸化决定T细胞效应功能的调控机制。本项目将利用定量质谱等前沿技术研究抗原刺激所引发的特异性TCR磷酸化模式及其下游信号通路模式；利用单分子等前沿手段研究特异性TCR磷酸化模式产生的分子机制；利用肿瘤模型研究TCR磷酸化模式对T细胞抗原免疫应答的直接影响。该项目的执行将阐明T细胞抗原特异性免疫应答的调控机制并为相关疾病的治疗提供新的思路。

T cells play important roles in the process of inflammation, in particular chronic inflammation. T cells can specifically recognize antigens and initiate antigen-specific immune responses, which is largely dependent on T cell receptor (TCR) signaling. The ligation of TCR with its cognate antigen results in the tyrosine phosphorylation of the CD3 molecules in the TCR complex, thus triggering downstream signaling cascades to fully activate T cells. Different antigens can trigger distinct TCR signaling pathways that lead to different T cell immune responses. Our earlier works unveil the molecular mechanism of the maintenance of TCR quiescent state in resting T cells (Cell 2008, first author) and the amplification of TCR activating signal in activated T cells (Nature 2013, corresponding author). But we still do not know how antigen can directly determine the effector function of T cells via TCR phosphorylation patterns. In this project, we will use cutting-edge technologies including Quantitative Mass Spectrometry to study the antigen-induced TCR phosphorylation patterns and downstream signaling patterns. We will use single molecule and other technologies to investigate how TCR decodes different antigen stimulating signals to distinct TCR phosphorylation patterns. We will also use tumor models to study the physiological importance of TCR phosphorylation patterns in T cell immune responses. The performance of this project will elucidate the molecular mechanism of antigen-specific immune response of T cells and also provide new ideas for treating human diseases.