title: The dual effects of B cell depletion on antigen-specific T cells in BDC2.5NOD mice.
abstract: B cells play a critical role in the pathogenesis of autoimmune diabetes. To investigate the mechanisms by which B cell depletion therapy attenuates islet β cell loss and particularly to examine the effect of B cells on both diabetogenic and regulatory Ag-specific T cells, we generated a transgenic BDC2.5NOD mouse expressing human CD20 on B cells. This allowed us to deplete B cells for defined time periods and investigate the effect of B cell depletion on Ag-specific BDC2.5 T cells. We depleted B cells with anti-human CD20 Ab using a multiple injection protocol. We studied two time points, before and after B cell regeneration, to examine the effect on BDC2.5 T cell phenotype and functions that included antigenic response, cytokine profile, diabetogenicity, and suppressive function of regulatory T (T(reg)) cells. We found unexpectedly that B cell depletion induced transient aggressive behavior in BDC2.5 diabetogenic T cells and reduction in T(reg) cell number and function during the depletion period. However, after B cell reconstitution, we found that more regenerated B cells, particularly in the CD1d(-) fraction, expressed immune regulatory function. Our results suggest that the regenerated B cells are likely to be responsible for the therapeutic effect after B cell depletion. Our preclinical study also provides direct evidence that B cells regulate both pathogenic and T(reg) cell function, and this knowledge could explain the increased T cell responses to islet Ag after rituximab therapy in diabetic patients in a recent report and will be useful in design of future clinical protocols.
authors.affiliation: Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Xiang
authors.forename: Jian
authors.initials: J
authors.lastname: Peng
authors.forename: Ningwen
authors.initials: N
authors.lastname: Tai
authors.forename: Changyun
authors.initials: C
authors.lastname: Hu
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Zhou
authors.forename: F Susan
authors.initials: FS
authors.lastname: Wong
authors.forename: Li
authors.initials: L
authors.lastname: Wen
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D048909:Diabetes Complications / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D018951:Antigens, CD20; D018984:Epitopes, T-Lymphocyte