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 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 H 1 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.