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

: CD4 + T cells play a critical role in antiviral humoral and cellular immune responses. We have previously reported that subcutaneous lymphocytic choriomeningitis virus (s.c. LCMV) infection is characterized by a stark compartmentalization of CD4 + T cells, leading to strong T H 1 polarization but virtually absent T follicular helper (T FH ) cells, a key driver of humoral immunity. Here, we investigated the mechanisms responsible for this impaired T FH differentiation. We found that T-bet + cells induced by s.c. LCMV infection encompass a T H 1 subset expressing Granzyme-B (GzmB) and a Tcf-1 + subset that retains the potential for T FH differentiation without expressing mature T FH markers. Interestingly, IFN-γ blockade enables full differentiation of Tcf-1 + cells into T FH , formation of germinal centers and increased antibody production. Of note, the suppression of T FH cells by IFN-γ is not directly mediated through CD4 + T cells but rather involves another cell type, likely dendritic cells (DCs). Our study provides novel insights into the mechanisms directing early CD4 + T cell polarization and affecting humoral responses to viruses, laying a foundation for the development of effective vaccine strategies.