Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions

Abstract

IL-21- and CD40-dependent cognate interactions with T cells are identified as key drivers for the generation of IL-10-producing regulatory B cells, which can protect against autoimmune disease. Subsets of regulatory B cells have been identified in both mice and humans, including the regulatory B10 cell subset that produces the inhibitory cytokine interleukin-10 (IL-10). B-cell derived IL-10 can protect against autoimmune disease in mice. Here, Thomas Tedder and colleagues identify IL-21- and CD-40-dependent cognate interactions with T cells as key drivers for the generation of IL-10-producing CD5+ regulatory B cells. Transfer of in vitro-expanded regulatory B cells is shown to suppress signs of disease in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. This work suggests a novel strategy for the treatment of severe autoimmune diseases for which effective therapies are not available. B cells regulate immune responses by producing antigen-specific antibodies1. However, specific B-cell subsets can also negatively regulate T-cell immune responses, and have been termed regulatory B cells2,3,4. Human and mouse regulatory B cells (B10 cells) with the ability to express the inhibitory cytokine interleukin-10 (IL-10) have been identified2,3,4,5. Although rare, B10 cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmune diseases in mice5,6,7. How B10-cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression is unknown. Using a mouse model for multiple sclerosis, here we show that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells. Moreover, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease. The ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies.