Interferon gamma supresses T follicular helper cell and antibody responses upon viral infection

Abstract Although humoral and cellular immunity upon viral infections usually co-exist, sometimes one of the two responses emerges as dominant and is responsible for most of the antiviral activity. For example, vesicular 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 subcutaneous VSV infection inducing strong T FHpolarization that supports nAb responses, and subcutaneous LCMV in contrast promoting an extreme T H1 differentiation with no T FH. Single-cell RNA sequencing revealed that LCMV-specific T H1 cells comprise at least to distinct subsets, one of which expresses TCF1, which is usually expressed by T FH. We found that blocking of IFN gamma results in the transition of this atypical T-bet +TCF1 +cells into T FHcells, and in an increased number of germinal center B cells and antibodies. Our results identify IFN gamma as a molecular switch that suppresses T FHand antibody responses while supporting T H1 differentiation upon viral infection. This might be an additional mechanism whereby viruses like LCMV interfere with the generation of efficient antibody responses. Research was supported by the Italian Ministry of Education, University and Research grants SIR-RBSI14BAO5, PRIN-2017ZXT5WR and PRIN-20209Y5YFZ (to M.K.) and by the European Research Council (ERC) Consolidator Grant 725038 (to M.I.)