T cell-derived IFN-γ Suppresses T Follicular Helper Cell Differentiation and Antibody Responses during Viral Infections

Sala, E.; Nelli, M.; Laura, C.; Di Lucia, P.; Beccaria, C. G.; Bono, E. B.; Mangione, M.; Marotta, D.; Sperto, V.; Grillo, M.; Giustini, L.; Nie, J.; Furiato, G.; Malpighi, C.; Consolo, E.; David, E.; Cohen, M.; Giladi, A.; Amit, I.; Bosselut, R.; Guidotti, L. G.; Iannacone, M.; Kuka, M.

doi:10.1101/2024.12.31.630815

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bioRxiv · 10.1101/2024.12.31.630815

T cell-derived IFN-γ Suppresses T Follicular Helper Cell Differentiation and Antibody Responses during Viral Infections

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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 TH1 polarization but virtually absent T follicular helper (TFH) cells, a key driver of humoral immunity. Here, we investigated the mechanisms responsible for this impaired TFH differentiation. We found that T-bet+ cells induced by s.c. LCMV infection encompass a TH1 subset expressing Granzyme-B (GzmB) and a Tcf-1+ subset that retains the potential for TFH differentiation without expressing mature TFH markers. Interestingly, IFN-{gamma} blockade enables full differentiation of Tcf-1+ cells into TFH, formation of germinal centers and increased antibody production. Of note, the suppression of TFH cells by IFN-{gamma} is not directly mediated through CD4+ T cells but rather involves another cell type, likely dendritic cells (DCs). Our study provides novel insights into the mechanisms directing early CD4+ T cell polarization and affecting humoral responses to viruses, laying a foundation for the development of effective vaccine strategies.

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Sala, E., Nelli, M., Laura, C., Di Lucia, P., Beccaria, C. G., Bono, E. B., Mangione, M., Marotta, D., Sperto, V., Grillo, M., Giustini, L., Nie, J., Furiato, G., Malpighi, C., Consolo, E., David, E., Cohen, M., Giladi, A., Amit, I., Bosselut, R., Guidotti, L. G., Iannacone, M., Kuka, M.. 2025-01-01. T cell-derived IFN-γ Suppresses T Follicular Helper Cell Differentiation and Antibody Responses during Viral Infections. https://doi.org/10.1101/2024.12.31.630815

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