Regulatory B Cells in Mucosal Homeostasis and IBD

描述（由申请人提供）：遗传和过继转移实验证明了B细胞在粘膜免疫稳态和抵抗炎症性肠病中的意想不到的保护作用。然而，这种调节性B细胞群的身份和功能机制尚不清楚，它们在结肠炎生物分化模型中的作用也未被描述。我们的初步研究表明，表型不同的B细胞群在CD4CD45RBhi和Gai2-/- T细胞转移性结肠炎模型中介导保护作用。值得注意的是，这种保护需要CD8a+ T细胞，并且与中央CD8a T细胞和NK T细胞以及肠道CD4+CD8a+ DP T细胞的显著扩增有关。基于这些发现和最近的文献，我们提出调节性肠系膜B细胞，由于它们能够进入肠道抗原环境、BCR抗原特异性和细胞相互作用分子，能够非常熟练地激活与肠道抗原同源的NKT细胞群。激活后，这些NKT细胞驱动中枢和肠道dc的抗炎分化，使其无法诱导和激活结肠炎CD4 T细胞，而是促进非炎症性CD4CD8aa T细胞的分化。为了测试和完善这一模型，本研究将定义保护性B细胞群的表型和解剖位置，并使用遗传方法鉴定细胞相互作用和效应分子，通过这些分子实现它们的保护作用。扩增的T细胞亚群，以及中央和肠道树突状细胞，将被描述为激活状态和解剖丰度，并通过遗传手段评估其扩增所需的B细胞特征。直接细胞转移实验将确定B细胞在这些和两种生物分化性结肠炎系统中的保护作用是否需要这些细胞。

DESCRIPTION (provided by applicant): Genetic and adoptive transfer experiments demonstrate an unexpected protective role of B cells in mucosal immunologic homeostasis and resistance to inflammatory bowel disease. However, the identity and functional mechanisms of this regulatory B cell population are poorly understood, and their role in biologically divergent models of colitis are not delineated. Our preliminary studies reveal that a phenotypically distinct B cell population mediates protection in the CD4CD45RBhi and Gai2-/- T cell transfer colitis models. Notably, this protection requires CD8a+ T cells, and is associated with significant expansion of central CD8a T and NK T cells, and intestinal CD4+CD8a+ DP T cells. Based on these findings and recent literature, we propose that regulatory mesenteric B cells, due to their access to the enteric antigenic environment, BCR antigen specificity, and cell-interaction molecules, are exquisitely proficient for activation of an NKT cell population cognate for enteric antigens. Upon activation, these NKT cells drive the anti-inflammatory differentiation of central and intestinal DCs, who are rendered incompetent to induce and active colitigenic CD4 T cells, and instead promote the differentiation of non-inflammatory CD4CD8aa T cells. To test and refine this model, the present proposal will define the phenotype and anatomic location of the protective B cell populations, and use genetic methods to identify cell-interaction and effector molecules through which they carry out their protective effect. The expanded T cell subsets, and central and intestinal dendritic cells, will be characterized with regard to activation state and anatomic abundance, and by genetic means assess B cell traits required for their expansion. Direct cell transfer experiments will establish whether these cells are required for the protective effect of B cells in these and two biologically divergent colitis systems.