CD11c⁺ T-bet⁺ B Cells Require IL-21 and IFN-γ from Type 1 T Follicular Helper Cells and Intrinsic Bcl-6 Expression but Develop Normally in the Absence of T-bet

Abstract

CD11c⁺ T-bet⁺ B cells generated during ehrlichial infection require CD4⁺ T cell help and IL-21 signaling for their development, but the exact T cell subset required had not been known. In this study, we show in a mouse model of Ehrlichia muris that type 1 T follicular helper (T_FH1) cells provide help to CD11c⁺ T-bet⁺ B cells via the dual secretion of IL-21 and IFN-γ in a CD40/CD40L-dependent manner. T_FH1 cell help was delivered in two phases: IFN-γ signals were provided early in infection, whereas CD40/CD40L help was provided late in infection. In contrast to T-bet⁺ T cells, T-bet⁺ B cells did not develop in the absence of B cell–intrinsic Bcl-6 but were generated in the absence of T-bet. T-bet–deficient memory B cells were largely indistinguishable from their wild-type counterparts, although they no longer underwent switching to IgG2c. These data suggest that a primary function of T-bet in B cells during ehrlichial infection is to promote appropriate class switching, not lineage specification. Thus, CD11c⁺ memory B cells develop normally without T-bet but require Bcl-6 and specialized help from dual cytokine-producing T_FH1 cells.