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.