乙型肝炎病毒（HBV）会在HBV相关的肝细胞癌（HCC）中塑造T细胞免疫反应。T细胞可以被招募到细胞巢，但只有有限的T细胞特别参与对HBV相关肿瘤微环境（TME）和HBV抗原的特定反应。表观基因组计划如何调节病毒特异性免疫过程中的T细胞组分尚不清楚。我们开发了Ti-ATAC-seq.2，在54例HCC患者中，以细胞总数和单个细胞水平映射了αβ T细胞受体（TCR）库，表观基因组和转录组景观。我们深入研究了HBV特异性T细胞和特别对HBV抗原和HBV + TME做出反应的HBV相关T细胞亚群，表征了它们的TCR克隆性和特异性，并进行了表观基因组分析。一个共同的程序包括NFKB1/2、REL、NFATC2和NR4A1相关的独特TCR下游核心表观基因组和转录组调控元，普遍调控了HBV特异性Treg细胞和CD8+疲劳T（Tex）细胞的分化；这个程序也被选择性地富集在HBV相关Treg-CTLA4和CD8-Tex-TOX亚群中，并在HBV相关Treg-CTLA4亚群中推动更大的克隆扩张。54%的效应器和记忆HBV特异性T细胞都受到AP1、NFE2和BACH1/2的TF基序调控，这些基序以前已报道与病人无复发存活期延长相关。此外，HBV相关的肿瘤浸润性Treg与病人病毒滴度增加和糟糕预后相关。这项研究提供了从病毒感染和HBV + HCC独特的免疫耗竭中调节HBV相关T细胞分化和产生的表观基因组计划的细胞和分子基础的深入了解。Copyright © 2023 American Association for the Study of Liver Diseases.

Hepatitis B virus (HBV) shapes the T-cell immune responses in HBV-related hepatocellular carcinoma (HCC). T cells can be recruited to the nidus, but limited T cells participate specifically in response to the HBV-related tumor microenvironment (TME) and HBV antigens. How epigenomic programs regulate T-cell compartments in virus-specific immune processes is unclear.We developed Ti-ATAC-seq. 2 to map the T cell receptor (TCR) repertoire, epigenomic and transcriptomic landscape of αβ T cells at both the bulk-cell and single-cell levels in 54 HCC patients. We deeply investigated HBV-specific T cells and HBV-related T-cell subsets that specifically responded to HBV antigens and the HBV + TME, respectively, characterizing their TCR clonality and specificity, and performing epigenomic profiling. A shared program comprising NFKB1/2-, REL-, NFATC2- and NR4A1-associated unique TCR-downstream core epigenomic and transcriptomic regulomes, commonly regulated the differentiation of HBV-specific Treg cells and CD8 + exhausted T (Tex) cells; this program was also selectively enriched in the HBV-related Treg-CTLA4 and CD8-Tex-TOX subsets, and drove greater clonal expansion in HBV-related Treg-CTLA4 subset. 54% of the effector and memory HBV-specific T cells governed by TF motifs of AP1, NFE2, and BACH1/2, which have been previously reported to be associated with prolonged patient relapse-free survival. Moreover, HBV-related tumor-infiltrating Tregs correlated with both increased viral titer and poor prognosis in patients.This study provides insight into the cellular and molecular basis of the epigenomic programs that regulate the differentiation and generation of HBV-related T cells from viral infection and HBV + HCC unique immune exhaustion.Copyright © 2023 American Association for the Study of Liver Diseases.