IL-12 signaling drives the differentiation and function of a TH1-derived TFH1-like cell population

Abstract

Abstract CD4+ T follicular helper (TFH) cells play key roles in the generation of humoral immunity, as they provide T cell help to B cells that ultimately results in the production of pathogen-specific antibodies. A subset of TFH cells that shares features with TH1 cells, referred to as (TH1)-biased TFH (TFH1) cells, has recently been shown to play key roles in responses to chronic infections including HIV and malaria, as well as the onset of some autoimmune diseases. Despite the apparent importance of these cells to comprehensive immune responses and human health, many questions remain regarding their origin, including the molecular mechanisms that regulate their differentiation. Here, we describe a population of TH1-derived TFH1-like cells that produce both the TH1 cytokine interferon-γ and the TFH-associated cytokine interleukin-21 (IL-21). Interestingly, this TFH1-like population exhibits increased B cell helper activity compared to IL-6 derived TFH-like cells. We further demonstrate that IL-12 signaling is required for both the differentiation and functional properties of the TFH1-like cell population. Specifically, IL-12-dependent activation of STAT4, and unexpectedly STAT3, result in both the upregulation of the TFH lineage-defining transcription factor Bcl-6, as well as the increased production of IL-21. Finally, we show that IL-12 signaling is required for TFH1-like cell expression of Icos, a receptor that is critical for the ability of T cells to provide help to B cells. Taken together, our findings provide potential insight into the genesis and regulatory requirements of recently described TFH1 cells with emerging roles in human health and disease.