正在进行肝启动的CD8 + T细胞的动力学和基因组景观。

StephenW

Nature. 2019 Oct 2. doi: 10.1038/s41586-019-1620-6. [Epub ahead of print]
Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming.
Bénéchet AP1, De Simone G1,2, Di Lucia P1, Cilenti F2,3, Barbiera G3, Le Bert N4, Fumagalli V1,2, Lusito E3, Moalli F1, Bianchessi V2,3, Andreata F1, Zordan P1, Bono E1, Giustini L1, Bonilla WV5, Bleriot C6, Kunasegaran K4, Gonzalez-Aseguinolaza G7, Pinschewer DD5, Kennedy PTF8, Naldini L2,3, Kuka M1,2, Ginhoux F6,9, Cantore A2,3, Bertoletti A4,6, Ostuni R2,3, Guidotti LG1,2, Iannacone M10,11,12.
Author information

1
    Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
2
    Vita-Salute San Raffaele University, Milan, Italy.
3
    San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.
4
    Emerging Infectious Disease Program, Duke-NUS Medical School, Singapore, Singapore.
5
    Division of Experimental Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.
6
    Singapore Immunology Network, Singapore Agency for Science, Technology & Research (A∗STAR), Singapore, Singapore.
7
    Gene Therapy and Gene Regulation Program, Centre for Applied Medical Research, Pamplona, Spain.
8
    Barts Liver Centre, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.
9
    Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China.
10
    Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. [email protected].
11
    Vita-Salute San Raffaele University, Milan, Italy. [email protected].
12
    Experimental Imaging Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy. [email protected].

Abstract

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.

PMID:
    31582858
DOI:
    10.1038/s41586-019-1620-6

StephenW

性质。 2019年10月2日.doi：10.1038 / s41586-019-1620-6。 [Epub提前发布]
正在进行肝启动的CD8 + T细胞的动力学和基因组景观。
BénéchetAP1，De Simone G1,2，Di Lucia P1，Cilenti F2,3，Barbiera G3，Le Bert N4，Fumagalli V1,2，Lusito E3，Moalli F1，Bianchessi V2,3，Andreata F1，Zordan P1，Bono E1， Giustini L1，Bonilla WV5，Bleriot C6，Kunasegaran K4，Gonzalez-Aseguinolaza G7，Pinschewer DD5，Kennedy PTF8，Naldini L2,3，Kuka M1,2，Ginhoux F6,9，Cantore A2,3，Bertoletti A4,6，Ostuni R2 ，3，Guidotti LG1,2，Iannacone M10,11,12。
作者信息

1个
    IRCCS圣拉斐尔科学研究所免疫学，移植和传染病科，意大利米兰。
2
    维塔礼炮圣拉斐尔大学，意大利米兰。
3
    IRCCS圣拉斐尔Telethon基因治疗研究所（SR-TIGET），意大利米兰。
4
    新加坡，新加坡国立杜克大学医学院新兴传染病项目。
5
    瑞士巴塞尔大学巴塞尔大学生物医学系实验病毒学系。
6
    新加坡科学技术研究局（A ∗ STAR），新加坡免疫学网络，新加坡，新加坡。
7
    西班牙潘普洛纳应用医学研究中心基因治疗和基因调控计划。
8
    英国伦敦玛丽皇后大学Barts和伦敦医学院牙科学院Barts肝脏中心。
9
    上海交通大学医学院上海免疫研究所，上海
10
    IRCCS圣拉斐尔科学研究所免疫学，移植和传染病科，意大利米兰。 [email protected]。
11
    维塔礼炮圣拉斐尔大学，意大利米兰。 [email protected]。
12
    意大利米兰IRCCS圣拉斐尔科学研究所实验成像中心。 [email protected]。

抽象

CD8 + T细胞对诸如乙型肝炎病毒的反应范围从功能障碍到分化成效应细胞，但这些独特结果的基础机制仍知之甚少。在这里，我们显示由不是乙型肝炎天然靶标的库普弗细胞引发的CD8 + T细胞分化为效应细胞，这些效应细胞形成了分布在整个肝脏中的致密的血管外簇。相比之下，乙型肝炎的天然靶标是肝细胞引发的启动作用会导致CD8 + T细胞的局部活化和增殖，但不会分化为效应细胞。这些细胞形成运动性细胞的松散的血管内簇，这些簇在门静脉周围聚结。转录组和染色质可及性分析揭示了这些功能异常的CD8 + T细胞的独特特征，与疲惫或耐受的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的治疗来挽救，而是对IL-2产生反应。这些发现提示了针对慢性乙型肝炎感染的免疫治疗策略。

PMID：
    31582858
DOI：
    10.1038 / s41586-019-1620-6