CD4+ T cells license Kupffer cells to reverse CD8+ T cell dysfunction induced by hepatocellular priming
Valentina Venzin, Cristian G. Beccaría, Chiara Perucchini, Pietro Delfino, Elisa Bono, Leonardo Giustini, Federica Moalli, Marta Grillo, Valeria Fumagalli, Chiara Laura, Pietro Di Lucia, Katharina Reinhard, Jutta Petschenka, Tana Omokoko, Anna Celant, Sabrina Ottolini, Keigo Kawashima, Micol Ravà, Marco De Giovanni, Donato Inverso, Mirela Kuka, Patrick Kennedy, Martin Guilliams, Giulia Casorati, Federica Pedica, Maurilio Ponzoni, Uğur Şahin, Nina Le Bert, Antonio Bertoletti, Fulvia Vascotto, Luca G. Guidotti, Matteo Iannacone
Abstract
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. Here the authors show that CD4+ effector T cells prevent or reverse CD8+ T cell dysfunction by licensing Kupffer cells to trigger IL-27 production, defining a liver-specific immune circuit and a potential target for chronic HBV therapeutics.