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

Kleffel, Sonja, Vergani, Andrea, Tezza, Sara, Ben Nasr, Moufida, Niewczas, Monika A., Wong, Florence Susan ORCID: https://orcid.org/0000-0002-2812-8845, Bassi, Roberto, D'Addio, Francesca, Schatton, Tobias, Abdi, Reza, Atkinson, Mark, Sayegh, Mohamed H., Wen, Li, Wasserfall, Clive H., O'Connor, Kevin C. and Fiorina, Paolo 2014. Interleukin-10+ regulatory B cells arise within antigen-experienced CD40+B cells to maintain tolerance to islet autoantigens. Diabetes 64 (1) , pp. 158-171. 10.2337/db13-1639

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	American Diabetes Association
ISSN:	0012-1797
Date of Acceptance:	31 July 2014
Last Modified:	31 Oct 2022 10:23
URI:	https://orca.cardiff.ac.uk/id/eprint/84642

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