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Hepatology
Original article
Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection
Ruben C Hoogeveen1,2, Maxwell P Robidoux1, Tatjana Schwarz3, Laura Heydmann4, James A Cheney1, Daniel Kvistad1, Jasneet Aneja1, Juliana G Melgaço5, Carlos A Fernandes6, Raymond T Chung1, Andre Boonstra2, Arthur Y Kim7, Thomas F Baumert4, Jörg Timm3, Lia L Lewis-Ximenez5, Pierre Tonnerre1, Georg M Lauer1
Author affiliations
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
Institute of Virology, Heinrich Heine University, University Hospital, Düsseldorf, Germany
Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm U1110, Strasbourg, France
Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil
Laboratório Central de Saúde Pública Noel Nutels, Rio de Janeiro, Brazil
Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
Correspondence to Dr Georg M Lauer, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston MA 02114, USA; [email protected]
Abstract
Objective Chronic HBV infection affects more than 250 million people worldwide and remains a global healthcare problem in part because we lack curative treatment. Sustained viral control requires HBV-specific T cells, but these become functionally impaired in chronic infection. Clinical evidence indicates that functional cure of HBV infection by the host immune response is feasible. Developing T cell-based therapies able to achieve functional cure will require identification of the requirements for a successful T cell response against HBV and the relative contribution of individual T cell specificities to HBV control.
Design The phenotype and function of HBV-specific T cells were studied directly ex vivo using fluorochrome-labelled multimers. We studied multiple HBV-specific T cell specificities targeting different HBV proteins in individuals with either an acute self-limiting or chronic HBV infection.
Results We detected strong T cell responses targeting multiple HBV viral proteins in acute self-limiting and low-frequency core and polymerase-specific T cells in chronic infection. Expression of the T cell inhibitory receptor PD-1, as well as T cell differentiation, T cell function and T cell regulation differed by stages and outcomes of infection. In addition, these features differed significantly between T cells targeting different HBV specificities.
Conclusion HBV-specific T cells with different target specificities are characterised by distinct phenotypical and functional profiles. These results have direct implications for the design of immunological studies in HBV infection, and are potentially relevant for informing immunotherapeutic approaches to induce functional cure.
Ruben C Hoogeveen1,2，Maxwell P Robidoux1，Tatjana Schwarz3，Laura Heydmann4，James A Cheney1，Daniel Kvistad1，Jasneet Aneja1，JulianaGMelgaço5，Carlos A Fernandes6，Raymond T Chung1，Andre Boonstra2，Arthur Y Kim7，Thomas F Baumert4，Jörg Timm3，Lia L Lewis-Ximenez5，Pierre Tonnerre1，Georg M Lauer1
作者隶属关系
马萨诸塞州综合医院消化内科和美国马萨诸塞州波士顿哈佛医学院
荷兰鹿特丹Erasmus MC消化内科和肝病学系
德国杜塞尔多夫大学医院海因里希海涅大学病毒学研究所
Institut de Recherche sur les Maladies ViralesetHépatiques，Inserm U1110，Strasbourg，France
FundaçãoOswaldoCruz，Instituto Oswaldo Cruz，巴西里约热内卢
巴西里约热内卢巴西中央电力公司实验室
马萨诸塞州综合医院传染病科和美国马萨诸塞州波士顿哈佛医学院
与美国马萨诸塞州波士顿总医院和哈佛医学院消化内科Georg M Lauer博士的通信，美国波士顿，马萨诸塞州02114; [email protected]