Venzin Valentina, Beccaria Cristian G, Perucchini Chiara, Delfino Pietro, Bono Elisa B, Giustini Leonardo, Moalli Federica, Grillo Marta, Fumagalli Valeria, Laura Chiara, Di Lucia Pietro, Reinhard Katharina, Petschenka Jutta, Omokoko Tana Annmarie, Celant Anna, Ottolini Sabrina, Kawashima Keigo, Ravà Micol, De Giovanni Marco, Inverso Donato, Kuka Mirela, Kennedy Patrick T F, Guilliams Martin, Casorati Giulia, Pedica Federica, Ponzoni Maurilio, Şahin Uğur, Le Bert Nina, Bertoletti Antonio, Vascotto Fulvia, Guidotti Luca G, Iannacone Matteo
Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Vita-Salute San Raffaele University, Milan, Italy.
Nat Immunol. 2025 Jun 30. doi: 10.1038/s41590-025-02199-3.
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.
慢性乙型肝炎病毒（HBV）感染的特征是HBV特异性CD8 T细胞功能失调，恢复其效应活性是主要治疗目标。在此，我们构建了HBV特异性CD4 T细胞受体转基因小鼠，以表明CD4效应T细胞可预防并逆转由肝细胞致敏诱导的CD8⁺ T细胞功能障碍。这种挽救增强了抗病毒CD8 T细胞功能并抑制了病毒复制。CD4 T细胞的辅助作用直接在肝脏内发生，不依赖于二级淋巴器官，且需要局部抗原识别。库普弗细胞而非树突状细胞是关键的抗原呈递平台。CD4 T细胞通过CD40 - CD40L相互作用赋予库普弗细胞许可，触发白细胞介素（IL）-12和IL-27的产生。IL-12扩大了CD4 T细胞库，而IL-27对CD8 T细胞的挽救至关重要。外源性IL-27同样可恢复小鼠以及从慢性感染患者分离的T细胞中HBV特异性CD8 T细胞的功能。这些发现确定IL-27是慢性HBV感染中一个易于处理的免疫治疗靶点。
