T-cell-derived IFN-γ suppresses T follicular helper cell differentiation and antibody responses
CD4<sup>+</sup> 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<sup>+</sup> T cells, leading to strong T<sub>H</sub>1 cell polarization but virtually absent T follicular helper (T<sub>FH</sub>) cells, key drivers of humoral immunity. Here, we investigate the mechanisms responsible for this impaired T<sub>FH</sub> differentiation. We show that T-bet<sup>+</sup> cells induced by LCMV infection encompass a T<sub>H</sub>1 cell subset expressing granzyme B (GzmB), and a Tcf-1<sup>+</sup> cell subset that retains the potential for T<sub>FH</sub> differentiation without expressing mature T<sub>FH</sub> markers. Notably, IFN-γ blockade enables full differentiation of Tcf-1<sup>+</sup> cells into T<sub>FH</sub> cells, formation of germinal centers, and increased antibody production. Suppression of T<sub>FH</sub> cells by IFN-γ is not directly mediated by CD4<sup>+</sup> T cells but rather involves another cell type, likely dendritic cells (DCs). Our study provides novel insights into the mechanisms underlying early CD4<sup>+</sup> T-cell polarization and humoral responses to viruses, with the potential to facilitate the development of effective vaccine strategies.
Authors
- Amir Giladi (ORCID: https://orcid.org/0000-0002-5880-2845)
- Chiara Malpighi (ORCID: https://orcid.org/0000-0002-8325-0181)
- Marta Grillo (ORCID: https://orcid.org/0000-0001-9064-2274)
- Mirela Kuka (ORCID: https://orcid.org/0000-0001-9418-1559)
- Davide Marotta (ORCID: https://orcid.org/0000-0003-1918-050X)
- Elisa Bono (ORCID: https://orcid.org/0000-0002-5212-3446)
- Daehong Kim (ORCID: https://orcid.org/0000-0002-1253-8946)
- Cristian G. Beccaría (ORCID: https://orcid.org/0000-0001-9682-4415)
- Maria Nelli (ORCID: https://orcid.org/0009-0004-5006-0201)
- Eyal David (ORCID: https://orcid.org/0000-0002-9020-2364)
- Rémy Bosselut (ORCID: https://orcid.org/0000-0003-2033-1790)
- Merav Cohen (ORCID: https://orcid.org/0000-0001-5536-1418)
- Ido Amit (ORCID: https://orcid.org/0000-0003-2968-877X)
- Burkhard Becher (ORCID: https://orcid.org/0000-0002-1541-7867)
- Eleonora Consolo
- Luca G. Guidotti (ORCID: https://orcid.org/0000-0002-0205-2678)
- Pietro Di Lucia (ORCID: https://orcid.org/0000-0002-0726-1532)
- Leonardo Giustini
- Eleonora Sala (ORCID: https://orcid.org/0000-0001-5109-6362)
- Marta Mangione
- Matteo Iannacone (ORCID: https://orcid.org/0000-0002-9370-2671)
- Francesca Tosi
- Jia Nie (ORCID: https://orcid.org/0000-0002-3865-0143)
- Chiara Laura (ORCID: https://orcid.org/0000-0002-3949-2538)
- Giuliana Furiato
- Valentina Sperto
Institutions
- National Institutes of Health (US)
- Vita-Salute San Raffaele University (IT)
- Tel Aviv University (IL)
- University of Zurich (CH)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- Weizmann Institute of Science (IL)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1038/s44318-025-00414-3
- Citations
- 2
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- Gilead Sciences
- Vir Biotechnology
- European Commission
- Ministero della Salute
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro
- Ministero dell'Università e della Ricerca
- European Research Council
- Agenzia Italiana del Farmaco, Ministero della Salute