Autoregulatory B-1 cells (34.13)

Abstract

Abstract Immunological tolerance in the periphery is mediated by clonal inactivation mechanisms as well as by regulatory cells. Recent studies showed that high IL-10 producing B-cell subsets with varying phenotype can regulate different immune responses in numerous mouse models. We found that, in comparison to B-2 cells, peritoneal B-1a cells are hyporesponsive to TLR stimulation in proliferation and antibody secretion, but produce very high amounts of IL-10. We hypothesized that the high IL-10 levels work in an autocrine manner and autoregulate B-1 cells that are prone to produce autoantibodies. Accordingly, neutralization of IL-10 enhanced peritoneal B-1, but not splenic B-2 cell proliferation and differentiation to all TLRs tested. Moreover, IL-10-/- peritoneal B-1 B-cells responded better than wild type B-1 cells to TLR stimulation. Co-stimulation with CD40 and BAFF, but not IL-5, overcame the inhibitory effect of IL-10. The increased IL-10 production was unique to peritoneal B-1 B-cells, since splenic B-1 B cells behaved like splenic B-2 cells, in terms of IL-10 production and proliferation. This autoregulation appears to have physiological significance since IL-10 knock out peritoneal B-1 cells controlled Borrelia hermsii infection better than wild type B-1 cells. Thus the IL-10 mediated autoregulation of B-1 cells may have a role in the control of autoimmunity and infection. (Supported by NIH grants to SB).