病毒特异性T细胞的多因子异质性与人慢性乙型肝炎感染的进

StephenW

Sci Immunol. 2019 Feb 8;4(32). pii: eaau6905. doi: 10.1126/sciimmunol.aau6905.
Multifactorial heterogeneity of virus-specific T cells and association with the progression of human chronic hepatitis B infection.
Cheng Y1, Zhu YO2, Becht E1, Aw P2, Chen J1, Poidinger M1, de Sessions PF2, Hibberd ML2,3, Bertoletti A1,4, Lim SG5, Newell EW6,7.
Author information

1
    Singapore Immunology Network, Agency for Science, Technology and Research, Singapore.
2
    Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.
3
    Emerging Infectious Disease, Department of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, London, UK.
4
    Emerging Infectious Disease Program, Duke-NUS Medical School, Singapore.
5
    Division of Gastroenterology & Hepatology, National University Health System, Singapore.
6
    Singapore Immunology Network, Agency for Science, Technology and Research, Singapore. [email protected].
7
    Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Abstract

Associations between chronic antigen stimulation, T cell dysfunction, and the expression of various inhibitory receptors are well characterized in several mouse and human systems. During chronic hepatitis B virus (HBV) infection (CHB), T cell responses are blunted with low frequencies of virus-specific T cells observed, making these parameters difficult to study. Here, using mass cytometry and a highly multiplexed combinatorial peptide-major histocompatibility complex (pMHC) tetramer strategy that allows for the detection of rare antigen-specific T cells, we simultaneously probed 484 unique HLA-A*1101-restricted epitopes spanning the entire HBV genome on T cells from patients at various stages of CHB. Numerous HBV-specific T cell populations were detected, validated, and profiled. T cells specific for two epitopes (HBVpol387 and HBVcore169) displayed differing and complex heterogeneities that were associated with the disease progression, and the expression of inhibitory receptors on these cells was not linearly related with their extent of T cell dysfunction. For HBVcore169-specific CD8+ T cells, we found cellular markers associated with long-term memory, polyfunctionality, and the presence of several previously unidentified public TCR clones that correlated with viral control. Using high-dimensional trajectory analysis of these cellular phenotypes, a pseudo-time metric was constructed that fit with the status of viral infection in corresponding patients. This was validated in a longitudinal cohort of patients undergoing antiviral therapy. Our study uncovers complex relationships of inhibitory receptors between the profiles of antigen-specific T cells and the status of CHB with implications for new strategies of therapeutic intervention.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PMID:
    30737354
DOI:
    10.1126/sciimmunol.aau6905

StephenW

Sci Immunol。 2019年2月8日; 4（32）。 pii：eaau6905。 doi：10.1126 / sciimmunol.aau6905。
病毒特异性T细胞的多因子异质性与人慢性乙型肝炎感染的进展相关。
Cheng Y1，Zhu YO2，Becht E1，Aw P2，Chen J1，Poidinger M1，de Sessions PF2，Hibberd ML2,3，Bertoletti A1,4，Lim SG5，Newell EW6,7。
作者信息

1
    新加坡免疫学网络，新加坡科学，技术和研究机构。
2
    新加坡基因组研究所，新加坡科学，技术和研究机构。
3
    新兴传染病，病原体分子生物学系，伦敦卫生与热带医学学院，英国伦敦。
4
    新加坡杜克新加坡国立大学医学院新出现的传染病项目。
五
    新加坡国立大学卫生系统消化内科和肝病学系。
6
    新加坡免疫学网络，新加坡科学，技术和研究机构。 [email protected]。
7
    疫苗和传染病科，Fred Hutchinson癌症研究中心，西雅图，华盛顿州，美国。

抽象

在几种小鼠和人类系统中充分表征了慢性抗原刺激，T细胞功能障碍和各种抑制性受体的表达之间的关联。在慢性乙型肝炎病毒（HBV）感染（CHB）期间，观察到低频率的病毒特异性T细胞使T细胞反应迟钝，使得这些参数难以研究。在这里，我们使用质量细胞仪和高度多重组合肽 - 主要组织相容性复合物（pMHC）四聚体策略，允许检测罕见的抗原特异性T细胞，我们同时探测484个独特的HLA-A * 1101限制性表位跨越整个HBV来自CHB不同阶段患者的T细胞的基因组。检测，验证和分析了许多HBV特异性T细胞群。对两个表位（HBVpol387和HBVcore169）特异的T细胞显示出与疾病进展相关的不同和复杂的异质性，并且这些细胞上的抑制性受体的表达与它们的T细胞功能障碍的程度不是线性相关的。对于HBVcore169特异性CD8 + T细胞，我们发现与长期记忆，多功能性以及与病毒对照相关的几个先前未鉴定的公共TCR克隆的存在相关的细胞标志物。使用这些细胞表型的高维轨迹分析，构建了伪时间度量，其符合相应患者中病毒感染的状态。这在经历抗病毒治疗的纵向队列患者中得到验证。我们的研究揭示了抗原特异性T细胞谱与CHB状态之间抑制性受体的复杂关系，并探讨了新的治疗干预策略。

版权所有©2019作者，保留一些权利;独家许可证持有人美国科学促进会。没有对美国政府原创作品的要求。

结论：
    30737354
DOI：
    10.1126 / sciimmunol.aau6905