T-cell-derived IFN-γ suppresses T follicular helper cell differentiation and antibody responses

Abstract 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.