PD1在生发中心持续亲和力成熟与记忆细胞分化中的作用

Memory B cells are known to be derived from germinal centers, but the molecular mechanism that govern their generation remains elusive. Our previous research has identified memory B cell precursors in GCs (GC-MP) as cells that stop dividing but still express high levels of GC markers, such as Fas and GL7. This result suggests that exit from cell cycle might be one important prerequisite for GC cells to become long-lived memory cells. Follicular helper T cells have long been linked to the generation of GC-derived memory cells. To characterize their role in the process, we have compared GC-MP generation in T-dependent and T-independent GCs. We found that TI-GC lack the population of GC-MPs, indicating that T cells are absolutely required for the differentiation of memory cells. In addition, GC B cells proliferate faster, lack the light zone phenotype and collapse faster in the absence of T cells, implying that signals from T cells might regulate B cell cell cycle progression and GC maintenance. PD1 is a surface molecule that is highly upregulated in Tfh cells, and plays a generally negative role in regulating T cell function. However, previous research has shown that PD1 positively contribute to the maintenance of GCs and promotes memory and plasma cell formation. To resolve this apparent paradox, we hypothesize that PD1 reverse signaling arrest GC B cell cell cycle and induce the differentiation of quiescent memory cells, thus contributing to affinity maturation of antibody response. We will perform both in vitro and in vivo experiments to test this hypothesis, and evaluate the general role of PD1 signaling in GC maintenance, affinity maturation and memory cell differentiation.

生发中心是体液反应的重要组成部分，也是记忆B细胞与长效浆细胞产生的场所。稳定有效运转的生发中心以及高亲和力记忆B细胞的产生是现有疫苗产生效力的关键，但是目前人们对调控这些过程的关键分子知之甚少。我们通过对不依赖于T细胞的生发中心的研究发现，T细胞一方面延缓生发中心 B细胞的分裂，使其形成明区表型并持续运转；另一方面，可促进记忆B细胞的分化。我们同时发现，滤泡辅助T细胞表面的PD1受体在此过程中有关键作用。在T细胞参与的生发中心反应中阻断PD1通路可使生发中心B细胞增殖加快并失去明区表型。本项目旨在利用体内及体外手段进一步论证PD1在调控生发中心持续性亲和力成熟与记忆细胞分化中的作用，并阐明此通路在多克隆反应中的调控意义。