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

Multifactorial heterogeneity of virus-specific T cells and association with the progression of human chronic hepatitis B infection

    Yang Cheng1, Yuan O. Zhu2, Etienne Becht1, Pauline Aw2, Jinmiao Chen1, Michael Poidinger1, Paola Flórez de Sessions2, Martin Lloyd Hibberd2,3, Antonio Bertoletti1,4, Seng Gee Lim5 and Evan W. Newell1,6,*

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

    ↵*Corresponding author. Email: [email protected]


Mapping the T cell response to hepatitis B

Unlike evaluating antibody responses to infections, studying T cell responses has always been more complicated. A significant hurdle here continues to be the development of reagents to identify and characterize pathogen-specific T cells. Here, Cheng et al. have generated a comprehensive panel of peptide class I major histocompatibility complex tetramers to study CD8+ T cells that recognize hepatitis B virus (HBV). Using HBV-specific tetramers in conjunction with mass cytometry, they have documented functional states of HBV-specific CD8+ T cells in individuals with chronic HBV infection. The tetramer panels generated here to study HBV-specific T cells should be of broad utility to the HBV research community.
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.

StephenW

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

    Yang Cheng，Yuan O. Zhu2，Etienne Becht1，Pauline Aw2，Jinmiao Chen1，Michael Poidinger1，PaolaFlórezdeSessions2，Martin Lloyd Hibberd 2,3，Antonio Bertoletti1,4，Seng Gee Lim5和Evan W. Newell1,6，*

    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，新加坡科学技术研究局。
    3，英国伦敦伦敦卫生与热带医学学院病原体分子生物学系，感染传染病。
    4新加坡杜克 - 新加坡国立大学医学院的传染病计划。
    5新加坡国立大学卫生系统消化内科和肝病学分部。
    美国华盛顿州西雅图弗雷德哈钦森癌症研究中心6疫苗和传染病科

    ↵*通讯作者。电子邮件：[email protected]


绘制T细胞对乙型肝炎的反应

与评估抗体对感染的反应不同，研究T细胞反应一直比较复杂。这里的一个重要障碍仍然是开发用于鉴定和表征病原体特异性T细胞的试剂。在这里，程等人。已经产生了一组全面的肽类I类主要组织相容性复合物四聚体，以研究识别乙型肝炎病毒（HBV）的CD8 + T细胞。使用HBV特异性四聚体结合质量细胞计数，他们记录了慢性HBV感染患者中HBV特异性CD8 + T细胞的功能状态。这里生成的用于研究HBV特异性T细胞的四聚体组应该对HBV研究界具有广泛的用途。
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。