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<p>Chronic hepatitis B virus (HBV) infection is marked by dysfunctional HBV-specific CD8<sup>+</sup> T cells, and restoring their effector activity is a major therapeutic goal. Here, we generated HBV-specific CD4<sup>+</sup> T cell receptor transgenic mice to show that CD4<sup>+</sup> effector T cells can prevent and reverse the CD8⁺ T cell dysfunction induced by hepatocellular priming. This rescue enhances antiviral CD8<sup>+</sup> T cell function and suppresses viral replication. CD4<sup>+</sup> T cell help occurs directly within the liver, independent of secondary lymphoid organs, and requires local antigen recognition. Kupffer cells, rather than dendritic cells, are the critical antigen-presenting platform. CD4<sup>+</sup> T cells license Kupffer cells via CD40–CD40L interactions, triggering interleukin (IL)-12 and IL-27 production. IL-12 expands the CD4<sup>+</sup> T cell pool, while IL-27 is essential for CD8<sup>+</sup> T cell rescue. Exogenous IL-27 similarly restores HBV-specific CD8<sup>+</sup> T cell function in mice and in T cells isolated from chronically infected patients. These findings identify IL-27 as a tractable immunotherapeutic target in chronic HBV infection.</p>

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CD4+ T cells license Kupffer cells to reverse CD8+ T cell dysfunction induced by hepatocellular priming

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月30日

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  • Valentina Venzin,
  • Cristian G. Beccaria,
  • Chiara Perucchini,
  • Pietro Delfino,
  • Elisa B. Bono,
  • Leonardo Giustini,
  • Federica Moalli,
  • Marta Grillo,
  • Valeria Fumagalli,
  • Chiara Laura,
  • Pietro Di Lucia,
  • Katharina Reinhard,
  • Jutta Petschenka,
  • Tana Annmarie Omokoko,
  • Anna Celant,
  • Sabrina Ottolini,
  • Keigo Kawashima,
  • Micol Ravà,
  • Marco De Giovanni,
  • Donato Inverso,
  • Mirela Kuka,
  • Patrick T. F. Kennedy,
  • Martin Guilliams,
  • Giulia Casorati,
  • Federica Pedica,
  • Maurilio Ponzoni,
  • Uğur Şahin,
  • Nina Le Bert,
  • Antonio Bertoletti,
  • Fulvia Vascotto,
  • Luca G. Guidotti,
  • Matteo Iannacone

摘要

Chronic hepatitis B virus (HBV) infection is marked by dysfunctional HBV-specific CD8+ T cells, and restoring their effector activity is a major therapeutic goal. Here, we generated HBV-specific CD4+ T cell receptor transgenic mice to show that CD4+ effector T cells can prevent and reverse the CD8⁺ T cell dysfunction induced by hepatocellular priming. This rescue enhances antiviral CD8+ T cell function and suppresses viral replication. CD4+ T cell help occurs directly within the liver, independent of secondary lymphoid organs, and requires local antigen recognition. Kupffer cells, rather than dendritic cells, are the critical antigen-presenting platform. CD4+ T cells license Kupffer cells via CD40–CD40L interactions, triggering interleukin (IL)-12 and IL-27 production. IL-12 expands the CD4+ T cell pool, while IL-27 is essential for CD8+ T cell rescue. Exogenous IL-27 similarly restores HBV-specific CD8+ T cell function in mice and in T cells isolated from chronically infected patients. These findings identify IL-27 as a tractable immunotherapeutic target in chronic HBV infection.