title: Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells.
abstract: IL-10-producing B cells, also known as regulatory B cells (Bregs), play a key role in controlling autoimmunity. In this study, we report that chimeric mice specifically lacking IL-10-producing B cells (IL-10(-/-)B cell) developed an exacerbated arthritis compared with chimeric wild-type (WT) B cell mice. A significant decrease in the absolute numbers of Foxp3 regulatory T cells (Tregs), in their expression level of Foxp3, and a marked increase in inflammatory Th1 and Th17 cells were detected in IL-10(-/-) B cell mice compared with WT B cell mice. Reconstitution of arthritic B cell deficient (μMT) mice with different B cell subsets revealed that the ability to modulate Treg frequencies in vivo is exclusively restricted to transitional 2 marginal zone precursor Bregs. Moreover, transfer of WT transitional 2 marginal zone precursor Bregs to arthritic IL-10(-/-) mice increased Foxp3(+) Tregs and reduced Th1 and Th17 cell frequencies to levels measured in arthritic WT mice and inhibited inflammation. In vitro, IL-10(+/+) B cells established longer contact times with arthritogenic CD4(+)CD25(-) T cells compared with IL-10(-/-) B cells in response to Ag stimulation, and using the same culture conditions, we observed upregulation of Foxp3 on CD4(+) T cells. Thus, IL-10-producing B cells restrain inflammation by promoting differentiation of immunoregulatory over proinflammatory T cells.
authors.affiliation: Division of Medicine, Centre for Rheumatology Research, University College London, London W1T 4JF, United Kingdom.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Carter
authors.forename: Rita
authors.initials: R
authors.lastname: Vasconcellos
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Rosser
authors.forename: Calogero
authors.initials: C
authors.lastname: Tulone
authors.forename: Alba
authors.initials: A
authors.lastname: Muñoz-Suano
authors.forename: Masahito
authors.initials: M
authors.lastname: Kamanaka
authors.forename: Michael R
authors.initials: MR
authors.lastname: Ehrenstein
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Claudia
authors.initials: C
authors.lastname: Mauri
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D015704:CD4 Antigens / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10; D007371:Interferon-gamma