Microbe-driven Development of GALT

摘要 微生物区系是次级淋巴组织发育所必需的，包括肠道- 相关淋巴组织(GALT)。高尔特和微生物群之间的相互作用是 在兔中尤其重要，因为B细胞增殖并突变其V(D)J基因作为回应 选择共生菌。此外，因为利用VH1而被识别的VHA B细胞是 由于特定的共生菌，选择性地在高尔特中扩张。相比之下，其他B 指定为VHn的单元格不会在Galt中展开。VHA和VHn B细胞的主要区别在于 骨架区域(FR)1和3的外表面，我们认为VHA特异的氨基 FR1和FR3外表面的酸与TLR一起形成一个结合基序 通过MyD88传递信号，通过结合细菌细胞介导VHA B细胞的选择性增殖 表面分子。我们假设这种先天的、非抗原特异性的刺激 通过B细胞受体(BCR)促进VHA B细胞的选择性扩增 主要抗体曲目的多样化。在目标1中，我们将通过确定 高尔特中的细菌，选择性地结合并激活VHA，但不能激活VHn B细胞。Aim 2将测试是否 已识别的细菌在体内专门驱动VHA B细胞的扩张；在目标3中，我们将 探讨细菌刺激VHA B细胞的机制。结果将阐明一种 细菌与B细胞相互作用促进免疫发展的新机制 系统。

Abstract Microbiota are required for the development of secondary lymphoid tissues, including gut- associated lymphoid tissues (GALT). Interactions between GALT and the microbiota are especially important in rabbits, as B cells proliferate and mutate their V(D)J genes in response to select commensal bacteria. Further, VHa B cells, identified because they utilize VH1, are selectively expanded in GALT as a result of specific commensal bacteria. In contrast, other B cells, designated VHn, do not expand in GALT. VHa and VHn B cells differ primarily in the external surface of framework regions (FR) 1 and 3, and we propose that VHa-specific amino acids on the external surfaces of FR1 and FR3 form a binding motif that together with TLR signaling through MyD88, mediates selective expansion of VHa B cells by binding bacterial cell surface molecules. We hypothesize that this innate-like, non-antigen-specific stimulation through the B cell receptor (BCR) facilitates selective expansion of VHa B cells and diversification of the primary Ab repertoire. In Aim 1, we will test this hypothesis by identifying bacteria in GALT that selectively bind to and activate VHa but not VHn B cells. Aim 2 will test if the identified bacteria specifically drive expansion of VHa B cells in vivo; and in Aim 3, we will explore the mechanism by which the bacteria stimulate VHa B cells. The results will elucidate a new mechanism by which bacteria interact with B cells to promote development of the immune system.