title: Interleukin-10+ regulatory B cells arise within antigen-experienced CD40+ B cells to maintain tolerance to islet autoantigens.
abstract: Impaired regulatory B cell (Breg) responses are associated with several autoimmune diseases in humans; however, the role of Bregs in type 1 diabetes (T1D) remains unclear. We hypothesized that naturally occurring, interleukin-10 (IL-10)-producing Bregs maintain tolerance to islet autoantigens, and that hyperglycemic nonobese diabetic (NOD) mice and T1D patients lack these potent negative regulators. IgVH transcriptome analysis revealed that islet-infiltrating B cells in long-term normoglycemic (Lnglc) NOD, which are naturally protected from diabetes, are more antigen-experienced and possess more diverse B-cell receptor repertoires compared to those of hyperglycemic (Hglc) mice. Importantly, increased levels of Breg-promoting CD40(+) B cells and IL-10-producing B cells were found within islets of Lnglc compared to Hglc NOD. Likewise, healthy individuals showed increased frequencies of both CD40(+) and IL-10(+) B cells compared to T1D patients. Rituximab-mediated B-cell depletion followed by adoptive transfer of B cells from Hglc mice induced hyperglycemia in Lnglc human CD20 transgenic NOD mouse models. Importantly, both murine and human IL-10(+) B cells significantly abrogated T-cell-mediated responses to self- or islet-specific peptides ex vivo. Together, our data suggest that antigen-matured Bregs may maintain tolerance to islet autoantigens by selectively suppressing autoreactive T-cell responses, and that Hglc mice and individuals with T1D lack this population of Bregs.
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kleffel
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA Transplant Medicine, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vergani
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Sara
authors.initials: S
authors.lastname: Tezza
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Moufida
authors.initials: M
authors.lastname: Ben Nasr
authors.affiliation: Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Monika A
authors.initials: MA
authors.lastname: Niewczas
authors.affiliation: Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, U.K.
authors.forename: Susan
authors.initials: S
authors.lastname: Wong
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bassi
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA Transplant Medicine, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Addio
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schatton
authors.affiliation: Nephrology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Reza
authors.initials: R
authors.lastname: Abdi
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
authors.forename: Mark
authors.initials: M
authors.lastname: Atkinson
authors.affiliation: Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.affiliation: Department of Immunology, Yale School of Medicine, New Haven, CT.
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
authors.forename: Clive H
authors.initials: CH
authors.lastname: Wasserfall
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: O'Connor
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA Transplant Medicine, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milano, Italy paolo.fiorina@childrens.harvard.edu.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
mesh_terms: D000328:Adult; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D060151:B-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D059467:Transcriptome / Q000276:immunology; D055815:Young Adult
chemical_list: D001324:Autoantigens; D019013:CD40 Antigens; C508609:IL10 protein, human; C556062:IL10 protein, mouse; D016753:Interleukin-10