Regulatory B Cells Control T Cell Autoimmunity Through IL-21-Dependent Cognate Interactions

B cells regulate immune responses by producing antigen-specific antibody(1). However, specific B cell subsets can also negatively regulate immune responses, validating the existence of regulatory B cells(2–4). Human and mouse regulatory B cells (B10 cells) with the ability to express the inhibitory cytokine IL-10 have been identified(2–5). Although rare, B10 cells are potent negative regulators of antigen-specific inflammation and T cell-dependent autoimmune diseases in mice(5–7). How B10 cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression are unknown. Using a mouse model for multiple sclerosis, we show here 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 dramatically inhibit disease symptoms when transferred into mice with established autoimmune disease. Thereby, 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.