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_H1 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_H1 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.