B cells expressing IFN-γ suppress Treg-cell differentiation and promote autoimmune experimental arthritis

Clinical efficacy in the treatment of rheumatoid arthritis with anti-CD20 (Rituximab)-mediated B-cell depletion has garnered interest in the mechanisms by which B cells contribute to autoimmunity. We have reported that B-cell depletion in a murine model of proteoglycan-induced arthritis (PGIA) leads to an increase in Treg cells that correlate with decreased autoreactivity. Here, we demonstrate that the increase in Treg cells after B-cell depletion is due to an increase in the differentiation of naive CD4(+) Tcells into Treg cells. Since the development of PGIA is dependent on IFN- and B cells are reported to produce IFN-, we hypothesized that B-cell-specific IFN- plays a role in the development of PGIA. Accordingly, mice with B-cell-specific IFN- deficiency were as resistant to the induction of PGIA as mice that were completely IFN- deficient. Importantly, despite a normal frequency of IFN--producing CD4(+) Tcells, B-cell-specific IFN--deficient mice exhibited a higher percentage of Treg cells compared with that in WT mice. These data indicate that B-cell IFN- production inhibits Treg-cell differentiation and exacerbates arthritis. Thus, we have established that IFN-, specifically derived from B cells, uniquely contributes to the pathogenesis of autoimmunity through prevention of immunoregulatory mechanisms.