硫酸胆固醇对T细胞受体信号的调控机制

T cell receptor (TCR) determines the specificity of antigen recognition during adaptive immune responses. Specialized lipid metabolites are involved in regulating TCR signaling. In our previous studies, we have identified cholesterol sulfate (CS), a naturally occurring derivative of membrane cholesterol, as an inhibitor of TCR nanoclustering, in-turn impair TCR signaling. Here we propose to use FRET and biochemical methods to study the molecular interaction between CS and TCR, and examine the role of Ca2+ on this interaction. We will reveal the mechanism on how CS regulates TCR conformation change to establish a link between two fundamental models in TCR signaling, conformation change and nanoclustering. This study will advance our understanding of T cell antigen recognition and signaling, and provide the theoretical foundation for developing metabolite-based drugs to treat human autoimmune diseases and cancer.

T细胞受体（TCR）对外源抗原的识别是决定获得性免疫应答特异性的重要因素。细胞膜上的酯类代谢产物对TCR信号具有重要的调节作用。本课题组之前对胆固醇的天然衍生物硫酸胆固醇（Cholesterol Sulfate, CS）的研究发现，CS对TCR纳米簇的聚集具有负调节作用，并抑制TCR信号。在前期工作的基础上，本课题拟通过FRET技术和多种生化分析技术手段，研究CS与TCR的相互作用方式和对TCR膜结合构像的调控，以及钙离子在此过程中的作用，通过CS联系和统一TCR构像变化和纳米簇形成两种信号模型。这项研究将深化我们对T细胞抗原识别和信号的理解，为通过天然代谢产物调控T细胞免疫反应，进而治疗与免疫相关的人类疾病提供理论依据。