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 cell polarization but virtually absent T follicular helper (T_FH) cells, key drivers of humoral immunity. Here, we investigate the mechanisms responsible for this impaired T_FH differentiation. We show that T-bet⁺ cells induced by LCMV infection encompass a T_H1 cell subset expressing granzyme B (GzmB), and a Tcf-1⁺ cell subset that retains the potential for T_FH differentiation without expressing mature T_FH markers. Notably, IFN-γ blockade enables full differentiation of Tcf-1⁺ cells into T_FH cells, formation of germinal centers, and increased antibody production. Suppression of T_FH cells by IFN-γ is not directly mediated by CD4⁺ T cells but rather involves another cell type, likely dendritic cells (DCs). Our study provides novel insights into the mechanisms underlying early CD4⁺ T-cell polarization and humoral responses to viruses, with the potential to facilitate the development of effective vaccine strategies.