Interleukin-10+ regulatory b cells arise within antigen-experienced CD40+ B cells to maintain tolerance to islet autoantigens

Sonja Kleffel, Andrea Vergani, Sara Tezza, Moufida Ben Nasr, Monika A. Niewczas, Susan Wong, Roberto Bassi, Francesca D'Addio, Tobias Schatton, Reza Abdi, Mark Atkinson, Mohamed H. Sayegh, Li Wen, Clive H. Wasserfall, Kevin C. O'Connor, Paolo Fiorina

Research output: Contribution to journalArticlepeer-review

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 longterm 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. Rituximabmediated 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 isletspecific 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.

Original languageEnglish
Pages (from-to)158-171
Number of pages14
JournalDiabetes
Volume64
Issue number1
DOIs
Publication statusPublished - Jan 1 2015

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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