Interferon gamma suppresses T follicular helper cells and antibody responses upon viral infection

Humoral and cellular immunity upon viral infections usually co-exist; however, sometimes, one of the two responses emerges as dominant and is responsible for most of the antiviral activity. For example, infection with lymphocytic choriomeningitis virus (LCMV) induces very strong cellular responses, but weak and inefficient neutralizing Ab (nAb) responses. Lack of nAb responses is an important issue for complete clearance of LCMV and other similar viruses, which in some instances tend to establish chronic infections. Recent work from our group has shown that this unbalance is observed also at the level of CD4 T cells responses, with subcutaneous LCMV infection leading almost exclusively to TH1 but no TFH differentiation. Here, we report that LCMV-induced TH1 cells are heterogeneous and comprise a Tcf-1+ subset and a GzmB+ subset. We found that none of the subsets is dependent on the major TH1-polarizing cytokine IL-12. Instead, IFN-gamma (IFN-g) was found to promote the development of GzmB+ cells and to suppress the commitment of the Tcf-1+ population into fully differentiated TFH. As a result, blockade of IFN-g led to a rescue in the TFH population, germinal center B cells and antibody responses. Our results shed light on new mechanisms underlying the inefficient nAbs production in response to non-cytopathic viruses such as LCMV and are promising for the design of new vaccination strategies. scRNA-seq was performed on SMARTA CD4+ T cells which are specific for the MHC-II-restricted GP61-80 epitope of the LCMV glycoprotein. Naïve SMARTA CD4+ T cells were adoptively transferred into WT mice one day prior to s.c. intrafootpad infection with rLCMV and sorted from footpad-draining popliteal LNs (dLNs) five days after infection. To be able to compare transcriptional profiles of TH1 to those of TFH cells, we also sorted total SMARTA CD4+ T cells from dLNs of mice infected with rVSV, a recombinant VSV strain expressing the LCMV WE glycoprotein. Control SMARTA CD4+ T cells were isolated from naïve mice.