CD4+ T cells play a critical role in supporting antiviral humoral and cellular immune responses. Although these responses often coexist, one can sometimes dominate at the expense of the other. For instance, lymphocytic choriomeningitis virus (LCMV) induces a strong cellular immune response but generates a suboptimal neutralizing antibody (nAb) response, hindering viral clearance and enabling persistent infection. Recent findings indicate that this skewed preference toward cellular immunity is determined already during the differentiation of CD4+ T cells. Specifically, subcutaneous (s.c.) LCMV infection predominantly induces T-bet+ T helper 1 (TH1) differentiation while largely neglecting T follicular helper (TFH) differentiation, a key driver of humoral immunity. Here, we investigated the mechanisms responsible for this impaired TFH differentiation. We found that T-bet+ cells induced by s.c. LCMV infection are heterogeneous and encompass a terminally differentiated TH1 subset expressing Granzyme-B (GzmB) and a Tcf-1+ subset that retains the potential for TFH differentiation but that does not express CXCR5 and other mature TFH markers. Interestingly, T cell-derived IFN-γ facilitated the proliferation of the GzmB+ subset and inhibited Tcf-1+ cells' progression into TFH. The suppression of TFH cells by IFN-γ was not directly mediated through CD4+ T cells but rather involved another cell type, likely dendritic cells. Consistently, inhibition of IFN-γ enabled robust TFH differentiation, formation of germinal centers and increased antibody production. Our study provides novel insights into the mechanisms inhibiting nAb production in response to viruses and lays a foundation for the development of advanced vaccine strategies.

T cell-derived IFN-γ Suppresses T Follicular Helper Cell Differentiation and Antibody Responses during Viral Infections