Interleukin-10-Producing Plasmablasts Exert Regulatory Function in Autoimmune Inflammation

Abstract

B cells can suppress autoimmunity by secreting interleukin-10 (IL-10). Although subpopulations of splenic B lineage cells are reported to express IL-10 in vitro, the identity of IL-10-producing B cells with regulatory function in vivo remains unknown. By using IL-10 reporter mice, we found that plasmablasts in the draining lymph nodes (dLNs), but not splenic B lineage cells, predominantly expressed IL-10 during experimental autoimmune encephalomyelitis (EAE). These plasmablasts were generated only during EAE inflammation. Mice lacking plasmablasts by genetic ablation of the transcription factors Blimp1 or IRF4 in B lineage cells developed an exacerbated EAE. Furthermore, IRF4 positively regulated IL-10 production that can inhibit dendritic cell functions to generate pathogenic T cells. Our data demonstrate that plasmablasts in the dLNs serve as IL-10 producers to limit autoimmune inflammation and emphasize the importance of plasmablasts as IL-10-producing regulatory B cells.

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

“…42 IL-10 production by human plasmablasts has not been examined in detail, although a recent study suggested that human plasmablasts were a major source of B-cell-derived IL-10. 31 Previous studies provided evidence that IL-10-producing B cells had a transcriptional profile close to that of antibody-secreting cells and overexpressed PRDM1, IRF4, AICDA, and CD27 in human 60 and in murine models. 61 Our results show that human plasmablasts are enriched in IL-10-producing B cells.…”

“…11 Recent studies have shown that the latter cell subset bears regulatory properties and may be the main IL-10-producing B-cell subset in mice. [28][29][30][31] Discrepancies in the cell surface antigens studied and a lack of consensual definitions of the subset phenotypes limit the direct comparison of human B-cell subpopulation analyses. It is generally admitted that most human memory B cells are characterized by the expression of CD27 [32][33][34][35] and that human plasmablasts display a CD20 lo CD24 2 CD27 hi CD38 hi phenotype.…”

Human regulatory B cells in health and disease: therapeutic potential

“…Multiple subsets of B cells that produce IL-10, often with overlapping surface markers but diverse functions, have been reported and are collectively referred to as Bregs (12 + B cells, which have all been shown to suppress proinflammatory responses (4,(13)(14)(15)(16). Notably, fewer than 20% of the B cells within these different B cell subsets produce IL-10 and suppress immune responses.…”

“…One of the major limiting factors to using this approach is the lack of surface markers specific for Bregs. Although several markers, alone or in combination, have been shown to identify the majority of IL-10-producing Bregs, they are not sufficiently Breg-specific to use in cellular therapy (4,13,15,76). Identification of Breg-specific markers could result in the development of depletion therapies specifically targeting Bregs or effector B cells (Beffs).…”

Regulatory B cells promote graft-versus-host disease prevention and maintain graft-versus-leukemia activity following allogeneic bone marrow transplantation

“…10,11 Regulatory B cells (Bregs) are a newly described subset of B cells that appears to play important roles in autoimmunity. [12][13][14][15][16][17] Human Bregs were enriched in both transitional (CD24 …”