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Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming
Nature ( IF 50.5 ) Pub Date : 2019-10-02 , DOI: 10.1038/s41586-019-1620-6
Alexandre P Bénéchet 1 , Giorgia De Simone 1, 2 , Pietro Di Lucia 1 , Francesco Cilenti 2, 3 , Giulia Barbiera 3 , Nina Le Bert 4 , Valeria Fumagalli 1, 2 , Eleonora Lusito 3 , Federica Moalli 1 , Valentina Bianchessi 2, 3 , Francesco Andreata 1 , Paola Zordan 1 , Elisa Bono 1 , Leonardo Giustini 1 , Weldy V Bonilla 5 , Camille Bleriot 6 , Kamini Kunasegaran 4 , Gloria Gonzalez-Aseguinolaza 7 , Daniel D Pinschewer 5 , Patrick T F Kennedy 8 , Luigi Naldini 2, 3 , Mirela Kuka 1, 2 , Florent Ginhoux 6, 9 , Alessio Cantore 2, 3 , Antonio Bertoletti 4, 6 , Renato Ostuni 2, 3 , Luca G Guidotti 1, 2 , Matteo Iannacone 1, 2, 10
Nature ( IF 50.5 ) Pub Date : 2019-10-02 , DOI: 10.1038/s41586-019-1620-6
Alexandre P Bénéchet 1 , Giorgia De Simone 1, 2 , Pietro Di Lucia 1 , Francesco Cilenti 2, 3 , Giulia Barbiera 3 , Nina Le Bert 4 , Valeria Fumagalli 1, 2 , Eleonora Lusito 3 , Federica Moalli 1 , Valentina Bianchessi 2, 3 , Francesco Andreata 1 , Paola Zordan 1 , Elisa Bono 1 , Leonardo Giustini 1 , Weldy V Bonilla 5 , Camille Bleriot 6 , Kamini Kunasegaran 4 , Gloria Gonzalez-Aseguinolaza 7 , Daniel D Pinschewer 5 , Patrick T F Kennedy 8 , Luigi Naldini 2, 3 , Mirela Kuka 1, 2 , Florent Ginhoux 6, 9 , Alessio Cantore 2, 3 , Antonio Bertoletti 4, 6 , Renato Ostuni 2, 3 , Luca G Guidotti 1, 2 , Matteo Iannacone 1, 2, 10
Affiliation
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The responses of CD8+ T cells to hepatotropic viruses such as hepatitis B range from dysfunction to differentiation into effector cells, but the mechanisms that underlie these distinct outcomes remain poorly understood. Here we show that priming by Kupffer cells, which are not natural targets of hepatitis B, leads to differentiation of CD8+ T cells into effector cells that form dense, extravascular clusters of immotile cells scattered throughout the liver. By contrast, priming by hepatocytes, which are natural targets of hepatitis B, leads to local activation and proliferation of CD8+ T cells but not to differentiation into effector cells; these cells form loose, intravascular clusters of motile cells that coalesce around portal tracts. Transcriptomic and chromatin accessibility analyses reveal unique features of these dysfunctional CD8+ T cells, with limited overlap with those of exhausted or tolerant T cells; accordingly, CD8+ T cells primed by hepatocytes cannot be rescued by treatment with anti-PD-L1, but instead respond to IL-2. These findings suggest immunotherapeutic strategies against chronic hepatitis B infection.CD8+ T cells that are primed by hepatocytes differentiate into dysfunctional T cells, which can be rescued by treatment with IL-2.
中文翻译：
经历肝启动的 CD8+ T 细胞的动力学和基因组景观
CD8+ T 细胞对嗜肝病毒（如乙型肝炎）的反应范围从功能障碍到分化为效应细胞，但这些不同结果背后的机制仍然知之甚少。在这里，我们表明，不是乙型肝炎的天然靶标的枯否细胞的启动导致 CD8+ T 细胞分化为效应细胞，这些细胞形成密集的、血管外散布在整个肝脏中的不动细胞簇。相比之下，作为乙型肝炎的天然靶标的肝细胞的启动，会导致 CD8+ T 细胞的局部活化和增殖，但不会分化成效应细胞；这些细胞形成松散的血管内活动细胞簇，在门静脉周围聚集。转录组学和染色质可及性分析揭示了这些功能失调的 CD8+ T 细胞的独特特征，与耗尽或耐受的 T 细胞的重叠有限；因此，由肝细胞引发的 CD8+ T 细胞不能通过抗 PD-L1 治疗来挽救，而是对 IL-2 有反应。这些发现提示了针对慢性乙型肝炎感染的免疫治疗策略。由肝细胞引发的 CD8+ T 细胞分化为功能失调的 T 细胞，可以通过 IL-2 治疗来挽救。
更新日期：2019-10-02
中文翻译：
经历肝启动的 CD8+ T 细胞的动力学和基因组景观
CD8+ T 细胞对嗜肝病毒（如乙型肝炎）的反应范围从功能障碍到分化为效应细胞，但这些不同结果背后的机制仍然知之甚少。在这里，我们表明，不是乙型肝炎的天然靶标的枯否细胞的启动导致 CD8+ T 细胞分化为效应细胞，这些细胞形成密集的、血管外散布在整个肝脏中的不动细胞簇。相比之下，作为乙型肝炎的天然靶标的肝细胞的启动，会导致 CD8+ T 细胞的局部活化和增殖，但不会分化成效应细胞；这些细胞形成松散的血管内活动细胞簇，在门静脉周围聚集。转录组学和染色质可及性分析揭示了这些功能失调的 CD8+ T 细胞的独特特征，与耗尽或耐受的 T 细胞的重叠有限；因此，由肝细胞引发的 CD8+ T 细胞不能通过抗 PD-L1 治疗来挽救，而是对 IL-2 有反应。这些发现提示了针对慢性乙型肝炎感染的免疫治疗策略。由肝细胞引发的 CD8+ T 细胞分化为功能失调的 T 细胞，可以通过 IL-2 治疗来挽救。
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