IL-6 counteracts IL-2-dependent suppression of T follicular helper cell responses

Abstract

Abstract T follicular helper (Tfh) cells are a specialized subset of CD4+ T cells that aide in the production of high-affinity antibody (Ab) responses. In the absence of Tfh cells, there is impairment in the generation of protective Ab responses to pathogens. In autoimmune patients, however, the expansion of unwanted self-reactive Tfh cells favor auto-Ab responses and subsequent Ab-mediated pathology. Thus, understanding the factors that regulate the generation of Tfh cells is critical for developing more efficient vaccination strategies and for designing new therapeutic approaches to prevent Ab-mediated autoimmune diseases. In this regard, it is generally acknowledged that IL-2 inhibits CD4 T cells from differentiating into Tfh cells. Conversely, previous studies suggest that IL-6 signaling is required for normal Tfh cell responses. However, Tfh cells normally differentiate in the absence of IL-6 in some experimental models, suggesting that IL-6 is not absolutely necessary for Tfh cell formation. Thus, the exact role played by IL-6 in controlling Tfh cell responses remains elusive. Using an influenza infection model, we found that IL-6 is dispensable for the priming of influenza-specific Tfh cell precursors, but essential for the maintenance of the Tfh cells at the peak of the influenza immune response. Mechanistically, our results demonstrate that already differentiated Tfh cells produce large amounts of IL-2 in the GCs and that intrinsic IL-6 signaling is needed to antagonize the negative impact of IL-2 in the ongoing Tfh cell response. Collectively, our data demonstrate that IL-6 induces a program that allows for Tfh cells to produce IL-2 without succumbing to the deleterious effects of IL-2 on Tfh cell differentiation.