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<p>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&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月1日

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  • 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

摘要

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 cell polarization but virtually absent T follicular helper (TFH) cells, key drivers of humoral immunity. Here, we investigate the mechanisms responsible for this impaired TFH differentiation. We show that T-bet+ cells induced by LCMV infection encompass a TH1 cell subset expressing granzyme B (GzmB), and a Tcf-1+ cell subset that retains the potential for TFH differentiation without expressing mature TFH markers. Notably, IFN-γ blockade enables full differentiation of Tcf-1+ cells into TFH cells, formation of germinal centers, and increased antibody production. Suppression of TFH 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.