CCR2+中心记忆CD8 T细胞新亚群调节组织免疫反应的机制研究

Memory T cells are crucial for immune protection and can be broadly divided into three major subsets: the central memory (TCM) subset that circulates through lymphoid organs and proliferate upon antigen re-exposure to produce effector cells, the effector memory (TEM) subset that may circulate through non-lymphoid tissues and deliver immediate effector functions upon antigen re-challenge, and the tissue-resident memory (TRM) subset that permanently reside in non-lymphoid tissues to control infections locally. Our previous work identified a naturally arising polyclonal CCR2+ population of virtual TCM cells that develop soon after birth in response to self antigens. And these cells exhibit enhanced effector phenotype revealed by RNA sequencing analysis. Remarkably, during acute viral infection, virtual Tcm cells are pioneer cells that rapidly migrate into sites of infection with CCR2+Tvm accumulated. On this basis, we aim to uncover the mechanisms for the development and maintenance of this CCR2+Tvm population, as well as analyzing the effector functions in vivo and in vitro. Meanwhile, we would explore the early immune surveillance function by CCR2+Tvm in tissue. Taken together, we would reveal an unsuspected layer of sophistication in the division of labor among memory T cells and suggest CCR2+ pioneer Tvm cells as a pivotal strategy by which immune system utilizing self activities for the purpose of generating rapid and local responses toward invading pathogens during a primary infection.

记忆CD8 T细胞在宿主免疫反应中发挥重要保护作用：中心记忆T细胞(Tcm)循环于淋巴器官中并可再次响应抗原生成效应细胞；效应记忆T细胞(Tem)在非淋巴器官中循环并可迅速响应二次免疫反应；组织聚居记忆T细胞(Trm)长期滞留在外周组织中并发挥局部免疫控制作用。我们的前期工作发现，非免疫小鼠中自然发育产生的自身反应性多克隆中心记忆T细胞(virtual central memory, Tvm)具有表达CCR2的异质性分群。RNA测序分析显示该群细胞具有较强的效应功能。在病毒感染早期发现Tvm细胞快速侵入组织且CCR2+Tvm细胞群发生富集。本项目将在此基础上，深入研究CCR2+Tvm细胞的发育及维持机制，对其效应功能进行体内、体外多层面分析，并探索该群细胞如何参与早期组织免疫监控并产生免疫应答，揭示记忆T细胞发育、分工新机制，并阐明机体免疫系统通过利用自身反应性应对外来入侵的重要策略。