Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells

Abstract

The maintenance of immune tolerance to apoptotic cells (AC) within an inflammatory milieu is vital to prevent autoimmunity. To investigate this, we administered syngeneic AC i.v. into mice carrying a cohort of ovalbumin (OVA)-specific transgenic T cells (DO11.10) along with OVA peptide and complete Freund's adjuvant, observing a dramatic increase in OVA-specific IL-10 secretion. Activated splenic B cells responded directly to AC, increasing secretion of IL-10, and this programming by AC was key to inducing T cell-derived IL-10. We went on to ask whether AC are able to modulate the course of autoimmune-mediated, chronic inflammation. AC given up to 1 month before the clinical onset of collagen-induced arthritis protected mice from severe joint inflammation and bone destruction. Antigen-specific CD4+T cells again secreted significantly more IL-10, associated with a reduced titer of pathogenic anti-collagen II antibodies. Inhibition of IL-10 in vivo reversed the beneficial effects of AC. Passive transfer of B cells from AC-treated mice provided significant protection from arthritis. These data demonstrate that AC exert a profound influence on an adaptive immune response through the generation of CD19+regulatory B cells, which in turn are able to influence the cytokine profile of antigen-specific effector T cells.