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.
Interleukin-10+ regulatory b cells arise within antigen-experienced CD40+ B cells to maintain tolerance to islet autoantigens / S. Kleffel, A. Vergani, S. Tezza, M.B. Nasr, M.A. Niewczas, S. Wong, R. Bassi, F. D'Addio, T. Schatton, R. Abdi, M. Atkinson, M.H. Sayegh, L. Wen, C.H. Wasserfall, K.C. O'Connor, P. Fiorina, M. Ben Nasr. - In: DIABETES. - ISSN 0012-1797. - 64:1(2015), pp. 158-171.
|Titolo:||Interleukin-10+ regulatory b cells arise within antigen-experienced CD40+ B cells to maintain tolerance to islet autoantigens|
FIORINA, PAOLO (Ultimo) (Corresponding)
|Parole Chiave:||Adult; Animals; Antigens, CD40; Autoantigens; B-Lymphocytes, Regulatory; Diabetes Mellitus, Type 1; Female; Humans; Immune Tolerance; Interleukin-10; Islets of Langerhans; Male; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Middle Aged; Transcriptome; Young Adult; Internal Medicine; Endocrinology, Diabetes and Metabolism; Medicine (all)|
|Settore Scientifico Disciplinare:||Settore MED/13 - Endocrinologia|
|Data di pubblicazione:||2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.2337/db13-1639|
|Appare nelle tipologie:||01 - Articolo su periodico|