CD4+ T cells license Kupffer cells to reverse CD8+ T cell dysfunction induced by hepatocellular priming
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.
Authors
- Martin Guilliams (ORCID: https://orcid.org/0000-0003-3525-7570)
- Marta Grillo (ORCID: https://orcid.org/0000-0001-9064-2274)
- Patrick T.F. Kennedy (ORCID: https://orcid.org/0000-0001-9201-0094)
- Mirela Kuka (ORCID: https://orcid.org/0000-0001-9418-1559)
- Maurilio Ponzoni (ORCID: https://orcid.org/0000-0002-0055-325X)
- Keigo Kawashima (ORCID: https://orcid.org/0000-0003-0985-1111)
- Elisa Bono (ORCID: https://orcid.org/0000-0002-5212-3446)
- Cristian G. Beccaría (ORCID: https://orcid.org/0000-0001-9682-4415)
- Valentina Venzin (ORCID: https://orcid.org/0000-0002-9815-7887)
- Sabrina Ottolini (ORCID: https://orcid.org/0009-0003-2506-7121)
- Tana Omokoko
- Valeria Fumagalli (ORCID: https://orcid.org/0000-0003-2583-2498)
- Antonio Bertoletti (ORCID: https://orcid.org/0000-0002-2942-0485)
- Marco De Giovanni (ORCID: https://orcid.org/0000-0001-7521-3092)
- Donato Inverso (ORCID: https://orcid.org/0000-0003-0987-3345)
- Jutta Petschenka (ORCID: https://orcid.org/0000-0001-9475-6842)
- Giulia Casorati (ORCID: https://orcid.org/0000-0002-5102-4112)
- Luca G. Guidotti (ORCID: https://orcid.org/0000-0002-0205-2678)
- Chiara Perucchini (ORCID: https://orcid.org/0000-0003-3010-8576)
- Federica Moalli (ORCID: https://orcid.org/0000-0002-8426-2571)
- Katharina Reinhard (ORCID: https://orcid.org/0000-0001-8852-0091)
- Pietro Di Lucia (ORCID: https://orcid.org/0000-0002-0726-1532)
- Leonardo Giustini
- Fulvia Vascotto (ORCID: https://orcid.org/0000-0002-9839-3484)
- Micol Ravà (ORCID: https://orcid.org/0000-0001-7606-8368)
- Nina Le Bert (ORCID: https://orcid.org/0000-0003-0502-2527)
- Uğur Şahin (ORCID: https://orcid.org/0000-0003-0363-1564)
- Matteo Iannacone (ORCID: https://orcid.org/0000-0002-9370-2671)
- Pietro Delfino (ORCID: https://orcid.org/0000-0003-0119-0830)
- Federica Pedica (ORCID: https://orcid.org/0000-0003-0168-4718)
- Anna Celant (ORCID: https://orcid.org/0009-0008-8273-8004)
- Chiara Laura (ORCID: https://orcid.org/0000-0002-3949-2538)
Institutions
- Boehringer Ingelheim (Germany) (DE)
- Vita-Salute San Raffaele University (IT)
- Queen Mary University of London (GB)
- Johannes Gutenberg University Mainz (DE)
- University of Pavia (IT)
- Ghent University (BE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Duke-NUS Medical School (SG)
- BioNTech (Germany) (DE)
- VIB-UGent Center for Inflammation Research (BE)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
Publication Details
- Journal
- Nature Immunology
- Published
- 2025-06-30
- DOI
- https://doi.org/10.1038/s41590-025-02199-3
- Citations
- 13
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 10.37
Funders
- Associazione Italiana per la Ricerca sul Cancro