Intrinsic IFN-gamma-T-bet pathway mediates the generation of Th1-like regulatory T cells induced by CD40-activated B cells

Abstract

The plasticity of CD4+ T cell is found to be higher than previously thought and might be modified by the cross-talking among different signal pathways. On the other hand, the role of CD40-activated B cells in the differentiation of CD4+ T cell is still on debate and their underlying mechanism for inducing Tregs remains unknown. In this study, using coculture of human naïve CD4+CD25- T cells with allogeneic CD40-activated B cells without any exogenous cytokines, we have demonstrated that CD40-activated B cells could induce alloantigen-specific CD4hiCD25hi Tregs and Th1 cells from their naïve precursors under weak and optimal activation respectively. Interestingly, the induced CD4hiCD25hi Tregs had Th1 properties with high level of T-bet expression, and some of them produced IFN-gamma. Both IFN-gamma+ and IFN-gamma-CD4hiCD25hi Tregs had a similar alloantigen-specific suppressive capacity. Importantly, we further found that the endogenously produced IFN-gamma and intrinsic T-bet expression were involved in the generation of these CD4hiCD25hi Tregs but did not mediate their suppression by neutralization of IFN-gamma and interference of T-bet expression with siRNA. We concluded that the generation of these Th1-like Tregs was mediated by IFN-gamma-T-bet pathway and the stimulatory or tolerogenic role of CD40-activated B cells in CD4+ T-cell differentiation was dependent on the strength of the activation to T cells.