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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-GMPB (01))
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Hamilton, Frank A
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Li, Xiaoxiao; Braun, Jonathan; Wei, Bo (2011) Regulatory B cells in autoimmune diseases and mucosal immune homeostasis. Autoimmunity 44:58-68
Fujiwara, Daisuke; Chen, Ling; Wei, Bo et al. (2011) Small intestine CD11c+ CD8+ T cells suppress CD4+ T cell-induced immune colitis. Am J Physiol Gastrointest Liver Physiol 300:G939-47
Presley, Laura L; Wei, Bo; Braun, Jonathan et al. (2010) Bacteria associated with immunoregulatory cells in mice. Appl Environ Microbiol 76:936-41
Brewer, Sarah; Nair-Gill, Evan; Wei, Bo et al. (2010) Epithelial uptake of [18F]1-(2'-deoxy-2'-arabinofuranosyl) cytosine indicates intestinal inflammation in mice. Gastroenterology 138:1266-75
Wei, Bo; Wingender, Gerhard; Fujiwara, Daisuke et al. (2010) Commensal microbiota and CD8+ T cells shape the formation of invariant NKT cells. J Immunol 184:1218-26
McPherson, Michael; Wei, Bo; Turovskaya, Olga et al. (2008) Colitis immunoregulation by CD8+ T cell requires T cell cytotoxicity and B cell peptide antigen presentation. Am J Physiol Gastrointest Liver Physiol 295:G485-92
Wei, Bo; Su, Thomas T; Dalwadi, Harnisha et al. (2008) Resident enteric microbiota and CD8+ T cells shape the abundance of marginal zone B cells. Eur J Immunol 38:3411-25
Wei, Bo; McPherson, Michael; Turovskaya, Olga et al. (2008) Integration of B cells and CD8+ T in the protective regulation of systemic epithelial inflammation. Clin Immunol 127:303-12
Fujiwara, Daisuke; Wei, Bo; Presley, Laura L et al. (2008) Systemic control of plasmacytoid dendritic cells by CD8+ T cells and commensal microbiota. J Immunol 180:5843-52
Velazquez, Peter; Wei, Bo; McPherson, Michael et al. (2008) Villous B cells of the small intestine are specialized for invariant NK T cell dependence. J Immunol 180:4629-38

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