Hepatitis B surface antigen reduction is associated with hepatitis B core-specific CD8+ T cell quality

Frontiers in Immunology

Immunology

Masayuki Kurosaki¹  Shun Kaneko²  Takashi Honda³  Ryotaro Sakamori⁴  Tetsuo Takehara⁴  Miyako Murakawa⁵  Yasuhiro Asahina⁶  Tatsuya Kanto⁷  Sachiyo Yoshio⁷  Masaya Sugiyama⁸  Shokichi Takahama⁹  Yuji Masuta⁹  Hirotomo Murakami^1,10  Takuya Yamamoto^1,11  Victor Appay^1,12 

[1] Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan;Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan;Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan;Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan;Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan;Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan;Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan;Department of Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan;Department of Liver Diseases, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan;Department of Viral Pathogenesis and Controls, National Center for Global Health and Medicine, Tokyo, Japan;Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan;Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan;Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan;Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan;Laboratory of Translational Cancer Immunology and Biology, Next-generation Precision Medicine Research Center, Osaka International Cancer Institute, Osaka, Japan;The Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;Department of Virology and Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan;Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan;Université de Bordeaux, CNRS, Institut national de la santé et de la recherche médicale (INSERM), ImmunoConcEpT, UMR 5164, Bordeaux, France;

关键词: Chronic hepatitis B;    HBsAg;    HBV-specific CD8 + T cells;    scRNA-seq;    cytotoxicity;   

DOI  :  10.3389/fimmu.2023.1257113

 received in 2023-07-12, accepted in 2023-09-07,  发布年份 2023

来源: Frontiers

【 摘 要 】

Despite treatment, hepatitis B surface antigen (HBsAg) persists in patients with chronic hepatitis B (CHB), suggesting the likely presence of the virus in the body. CD8+ T cell responses are essential for managing viral replication, but their effect on HBsAg levels remains unclear. We studied the traits of activated CD8+ T cells and HBV-specific CD8+ T cells in the blood of CHB patients undergoing nucleos(t)ide analog (NUC) therapy. For the transcriptome profiling of activated CD8+ T cells in peripheral blood mononuclear cells (PBMCs), CD69+ CD8+ T cells were sorted from six donors, and single-cell RNA sequencing (scRNA-seq) analysis was performed. To detect HBV-specific CD8+ T cells, we stimulated PBMCs from 26 donors with overlapping peptides covering the HBs, HBcore, and HBpol regions of genotype A/B/C viruses, cultured for 10 days, and analyzed via multicolor flow cytometry. scRNA-seq data revealed that CD8+ T cell clusters harboring the transcripts involved in the cytolytic functions were frequently observed in donors with high HBsAg levels. Polyfunctional analysis of HBV-specific CD8+ T cells utilized by IFN-γ/TNFα/CD107A/CD137 revealed that HBcore-specific cells exhibited greater polyfunctionality, suggesting that the quality of HBV-specific CD8+ T cells varies among antigens. Moreover, a subset of HBcore-specific CD8+ T cells with lower cytolytic potential was inversely correlated with HBsAg level. Our results revealed a stimulant-dependent qualitative difference in HBV-specific CD8+ T cells in patients with CHB undergoing NUC therapy. Hence, the induction of HBcore-specific CD8+ T cells with lower cytolytic potential could be a new target for reducing HBsAg levels.

【 授权许可】

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Copyright © 2023 Takahama, Yoshio, Masuta, Murakami, Sakamori, Kaneko, Honda, Murakawa, Sugiyama, Kurosaki, Asahina, Takehara, Appay, Kanto and Yamamoto