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具有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知之甚少，它们在结肠炎生物学上不同的模型中的作用也没有被描述。我们的初步研究表明，表型不同的B细胞群体介导了CD 4 CD 45 RBhi和Gai 2-/- T细胞转移结肠炎模型中的保护作用。值得注意的是，这种保护需要CD 8a + T细胞，并且与中心CD 8a T和NK T细胞以及肠CD 4 + CD 8a + DP T细胞的显著扩增相关。基于这些发现和最近的文献，我们提出，由于其进入肠道抗原环境，BCR抗原特异性和细胞相互作用分子，调节性肠系膜B细胞，是非常熟练的肠抗原同源的NKT细胞群的激活。在活化后，这些NKT细胞驱动中枢和肠DC的抗炎分化，使其不能诱导和活化结肠炎性CD 4 T细胞，而是促进非炎性CD 4 CD 8aa T细胞的分化。为了测试和完善该模型，本建议将定义保护性B细胞群体的表型和解剖位置，并使用遗传学方法来鉴定细胞相互作用和效应分子，它们通过这些分子实现其保护作用。扩增的T细胞亚群以及中枢和肠树突细胞将在活化状态和解剖学丰度方面进行表征，并通过遗传手段评估其扩增所需的B细胞性状。直接细胞转移实验将确定这些细胞是否是B细胞在这些和两个生物学上不同的结肠炎系统中的保护作用所必需的。

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.