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

Eleonora Sala, Maria Nelli, Chiara Laura, Pietro Di Lucia, Cristian Gabriel Beccaria, Elisa B Bono, Marta Mangione, Davide Marotta, Valentina Sperto, Marta Grillo, Leonardo Giustini, Fabio Tosi, Jia Nie, Daehong Kim, Giuliana Furiato, Chiara Malpighi, Eleonora Consolo, Burkhard Becher, Eyal David, Merav Cohen, Amir Giladi, Ido Amit, Remy Bosselut, Luca G Guidotti, Matteo Iannacone, Mirela Kuka

Source abstract

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.