IL-12 signaling drives the differentiation and function of a T_H1-derived T_FH1-like cell population

CD4⁺ T follicular helper (T_FH) cells provide help to B cells and promote antibody-mediated immune responses. Increasing evidence supports the existence of T_FH populations that secrete cytokines typically associated with the effector functions of other CD4⁺ T cell subsets. These include T helper 1 (T_H1)-biased T_FH (T_FH1) cells that have recognized roles in both immune responses to pathogens and also the pathogenesis of autoimmune disease. Given their apparent importance to human health, there is interest in understanding the mechanisms that regulate T_FH1 cell formation and function. However, their origin and the molecular requirements for their differentiation are unclear. Here, we describe a population of murine T_H1-derived, T_FH1-like cells that express the chemokine receptor Cxcr3 and produce both the T_H1 cytokine interferon-γ and the T_FH-associated cytokine interleukin-21 (IL-21). Furthermore, these T_FH1-like cells promote B cell activation and antibody production at levels indistinguishable from conventional IL-6-derived T_FH-like cells. Regarding their regulatory requirements, we find that IL-12 signaling is necessary for the differentiation and function of this T_FH1-like cell population. Specifically, IL-12-dependent activation of STAT4, and unexpectedly STAT3, promotes increased expression of IL-21 and the T_FH lineage-defining transcription factor Bcl-6 in T_FH1-like cells. Taken together, these findings provide insight into the potential origin and differentiation requirements of T_FH1 cells.