意大利圣拉斐尔科学研究所Matteo Iannacone研究团队报道了CD4⁺ T细胞允许Kupffer细胞逆转由肝细胞启动诱导的CD8⁺ T细胞功能障碍。这一研究成果发表在2025年6月30日出版的国际学术期刊《自然—免疫学》上。

研究人员产生了HBV特异性CD4⁺ T细胞受体转基因小鼠，以证明CD4⁺效应T细胞可以预防和逆转CD8肝细胞启动诱导的T细胞功能障碍。这种拯救增强了抗病毒CD8⁺ T细胞功能并抑制病毒复制。CD4⁺ T细胞帮助直接发生在肝脏内，不依赖于次级淋巴器官，需要局部抗原识别。库普弗细胞，而不是树突状细胞，是关键的抗原呈递平台。CD4⁺ T细胞通过CD40-CD40L相互作用激活Kupffer细胞，触发白细胞介素(IL)-12和IL-27的产生。IL-12扩大CD4⁺ T细胞库，而IL-27对CD8⁺ T细胞的救援至关重要。外源性IL-27在小鼠和从慢性感染患者分离的T细胞中类似地恢复HBV特异性CD8⁺ T细胞功能。这些发现确定了IL-27是慢性HBV感染的一个可处理的免疫治疗靶点。

据了解，慢性乙型肝炎病毒（HBV）感染以HBV特异性CD8⁺ T细胞功能失调为特征，恢复其效应活性是主要的治疗目标。

附：英文原文

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

Author: 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, Rav, Micol, De Giovanni, Marco, Inverso, Donato, Kuka, Mirela, Kennedy, Patrick T. F., Guilliams, Martin, Casorati, Giulia, Pedica, Federica, Ponzoni, Maurilio, ahin, Uur, Le Bert, Nina, Bertoletti, Antonio, Vascotto, Fulvia, Guidotti, Luca G., Iannacone, Matteo

Issue&Volume: 2025-06-30

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.

DOI: 10.1038/s41590-025-02199-3

Source: https://www.nature.com/articles/s41590-025-02199-3