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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK069434-01
Application #
6853331
Study Section
Special Emphasis Panel (ZRG1-GMPB (01))
Program Officer
Hamilton, Frank A
Project Start
2005-03-15
Project End
2009-02-28
Budget Start
2005-03-15
Budget End
2006-02-28
Support Year
1
Fiscal Year
2005
Total Cost
$292,917
Indirect Cost
Name
University of California Los Angeles
Department
Pathology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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

Showing the most recent 10 out of 17 publications