IL-10-independent regulatory role for B cells in suppressing autoimmunity through GITRL-mediated maintenance of Tregs (176.18)

Abstract A regulatory role for B cells has been shown in animal models of autoimmunity and several studies suggested an IL-10-dependent mechanism. In our model of experimental autoimmune encephalomyelitis (EAE), WT mice exhibited a monophasic disease and recovered, but B cell deficiency, either genetic (µMT) or anti-CD20-mediated, led to unresolved EAE. Although B cells regulated EAE, we did not detect IL-10-producing B cells. Hence, we investigated IL-10-independent roles for B cells in immune regulation. B cell deficiency resulted in reduced numbers of CD4+Foxp3+ T regulatory cells (Tregs) in the periphery, suggesting involvement of B cells in their peripheral homeostasis. Interestingly, B cell depletion therapy in humans has been associated with the onset of autoimmunity. Likewise, reduction of Tregs post anti-CD20-mediated depletion of B cells resulted in spontaneous EAE and accelerated colitis in genetically susceptible mice. To study B cell-Treg interactions, we transferred B cells into µMT mice, which resulted in the proliferation and partial restoration of Treg numbers, sufficient for the resolution of EAE. Mechanistically, expression of glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL) by B cells was required, but IL-10 and B7 molecules were dispensable. Our results demonstrate a novel IL-10-independent role for B cells in regulating autoimmunity by maintenance of Tregs via GITRL.