T细胞信号在生发中心B细胞发育分化中的作用

It has been well established that collaborative interactions between T helper cells and B-cells are necessary for the generation of memory B cells in germinal centers (GCs). However, the molecular mechanisms by which helper T-cells support B-cell survival and functional differentiation are not well defined. To date, signaling through CD40-CD40L interaction is the only established receptor-ligand signaling pathway between B-cells and helper T-cells. We found that reverse signaling via ICOSL on B-cells can activate B-cells and synergizes with other B-cell activating signals. Reverse ICOSL signaling on GC B-cells is essential and sufficient to promote GC B-cell survival and functional maturation. Reverse ICOSL signaling in B-cells activates the transcription factor NFκB and regulates the MAPK signaling pathways that control cell survival and function. In vivo administration of soluble ICOS-Ig into ICOS-deficient mice largely corrects immune deficiency in ICOS mutant mice. Thus, our findings demonstrate that reverse signaling through ICOSL is essential for B-cell survival and functional maturation. This project proposes the following specific aims. (1) Define the cytoplasmic residues and motifs critical for ICOSL-mediated signal transduction in B-cells; (2) Dissect the ICOSL-induced signaling cascades leading to the activation of NF-κB and MAPK pathways; (3) Study the in vivo role of ICOS-mediated signaling in regulating T-dependent antibody responses.

T－B细胞间相互作用对于成熟后的B细胞进一步分化为效应B细胞至关重要。 辅助性T细胞和B细胞的相互作用是记忆性B细胞产生不可或缺的条件之一。 生发中心中T细胞对B细胞的存活和功能性分化的辅助作用，特别是其分子机制依旧不清楚。我们的研究表明，辅助性T细胞可以通过受体ICOS和配体ICOSL 的相互作用向B细胞提供辅助信共刺激分子信号介导的双向信号同时刺激T辅助细胞和生发中心B细胞的形成和分化。本课题将重点探索ICOS－ICOSL这对共刺激分子中，直接作用于B细胞的反向信号在生发中心B细胞存活及其向浆细胞和记忆B细胞分化过程中的分子机制。