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.

Altered Peripheral B-Lymphocyte Subsets in Type 1 Diabetes and Latent Autoimmune Diabetes in Adults

“…The observed B10 cell reduction could contribute to the breakdown of self-tolerance that leads to β-cell destruction in patients with T1D (24) or LADA. Antigen-activated IL-10–producing B cells may selectively inhibit autoreactive T-cell responses to islet-specific antigen to maintain self-tolerance, and hyperglycemic NOD mice and patients with T1D lack this population of regulatory B cells (37). In the clinical trial where B cells in patients with new-onset T1D were depleted, the patients showed a transient remission (8).…”

Immunogenetics of type 1 diabetes mellitus

“…More recently, it has been shown that antigen-matured Bregs may maintain tolerance to islet autoantigens by selectively suppressing autoreactive T-cell responses (Kleffel et al, 2014). In the context of T1DM pathogenesis, the inflammatory microenvironment may render this B cell subset functionally impaired or apoptotic.…”

Transient BAFF Blockade Inhibits Type 1 Diabetes Development in Nonobese Diabetic Mice by Enriching Immunoregulatory B Lymphocytes Sensitive to Deletion by Anti-CD20 Cotherapy

“…Thus, we hypothesized the B-lymphocytes that survive or rebound in NOD mice transiently treated with BAFFR-Fc alone might become enriched for a B reg -like population, but this protective population(s) is sensitive to deletion by co-infused anti-CD20. To date, the ability of B-lymphocytes to exert regulatory functions suppressing diabetogenic T-cells in NOD mice is reported to primarily occur through IL-10 production (7). Indeed, a significantly higher proportion B-lymphocytes capable of producing IL-10 upon LPS stimulation (B 10 cells) were recovered from mice transiently treated with BAFFR-Fc than ctrl mAb (Figure 4B).…”

“…This appears to result from B-lymphocytes expressing plasma membrane-bound autoreactive Ig molecules that can efficiently capture specific ß-cell antigens for subsequent display to diabetogenic T-cells, expanding such pathogenic effectors more efficiently than other APC subtypes (2–6). In contrast, a subset of B-lymphocytes may normally also play a T1D inhibitory regulatory role that could be defective in NOD mice and human patients (7). These observations place B-lymphocytes at an important nexus between the activation or inhibition of diabetogenic immune responses.…”

“…IL-10 producing B-lymphocytes (B 10 cells) have been reported to ameliorate disease development in mouse models of SLE (26), experimental autoimmune encephalitis (EAE) (27), and RA (28). It has also been reported a subset of B 10 cells, decreased in hyperglycemic NOD mice and T1D patients, play an immunoregulatory role in long-term disease protection (7). However, the capacity of B-lymphocyte depletion to modulate levels of B 10 cells in the context of T1D is currently unknown.…”