IFN-γ promotes TH1 at the expense of TFH differentiation during viral infections

Abstract

Abstract Although humoral and cellular immunity upon viral infections usually co-exist, sometimes one of the two responses emerges and is responsible for most of the antiviral activity. For example, vescicular stomatitis virus (VSV) infection induces early and potent neutralizing antibody (nAb) responses, whereas lymphocytic choriomeningitis virus (LCMV) infection induces strong cellular responses, but weak nAb responses. Recent work from our laboratory has shown that unbalance is observed also at the level of CD4 T cells responses, with VSV inducing strong TFH polarization that support nAb responses, and LCMV in contrast promoting TH1 differentiation. Analysis of the VSV and LCMV priming niches led to identification of the spatiotemporal regulation of type I IFN expression as a critical regulator of antiviral CD4+ T cell polarization, with early type I IFN sensing leading to TFH polarization. Notably, this mechanism did not explain the strong TH1 differentiation observed during LCMV infection. In this study we aimed to elucidate the role of known TH1-polarizing cytokines in CD4+ T cell differentiation upon LCMV infection. We found that IFN-γ, but not IL-12, plays a key role in early CD4+ T cell differentiation upon LCMV infection, inducing TH1 cell polarization and suppressing TFH cell development, thus resulting in a shift in the equilibrium towards TFH and humoral responses. Future studies will determine the cellular source for this TH1-polarizing cytokine and the mechanism by which IFN-γ exerts its function, possibly unveiling the mechanisms underlying the reduced humoral response in the context of viral infections like LCMV.