Deep immune profiling by mass cytometry links human T and NK cell differentiation and cytotoxic molecule expression patterns.
Deep immune profiling by mass cytometry links human T and NK cell differentiation and cytotoxic molecule expression patterns.
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DOI：
10.1016/j.jim.2017.03.009
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发表时间：
2018-03
影响因子：
2.2
通讯作者：
Wherry EJ
中科院分区：
文献类型：
--
作者：
Bengsch B;Ohtani T;Herati RS;Bovenschen N;Chang KM;Wherry EJ
通过直接裂解消除感染细胞或肿瘤细胞是关键的T和NK细胞效应子功能。T细胞和NK细胞可通过协调分泌含有一种或两种成孔蛋白、穿孔素和颗粒溶素以及颗粒酶（Gzm）家族效应蛋白酶（在人中：Gzm A、B、K、M和H）的组合的细胞毒性颗粒来杀死靶细胞。了解细胞毒性分子的表达模式以及与T细胞和NK细胞不同状态的关系可能与自身免疫、感染性疾病和癌症中的免疫应答直接相关。然而，能够同时评估具有关于T和NK分化状态的详细信息的多种细胞毒性分子的表达的方法仍然有限。在这里，我们建立了一个高维度的质量细胞计数方法，全面询问细胞毒性程序和淋巴细胞分化的单细胞蛋白质组表达。该测定鉴定了与CD 8 T细胞分化阶段相关的细胞毒性分子的协调表达模式。穿孔素、颗粒溶解素、Gzm A、Gzm B和Gzm M的协调高表达与晚期效应记忆分化的标志物和趋化因子受体CX 3 CR 1的表达相关。然而，经典的门控和降维方法还鉴定了CD 8 T细胞中细胞毒性分子表达的其他不一致模式，包括穿孔素减少，但Gzm A、Gzm K和Gzm M表达高。当应用于非CD 8 T细胞时，该测定法鉴定了CD 56 hi与CD 56 dim上细胞毒性分子共表达的不同模式，所述细胞毒性分子共表达定义了NK细胞发育阶段;在CD 4 T细胞中，细胞毒性分子的低表达主要见于TH 1表型细胞中，但不见于T细胞或T滤泡辅助细胞（TFH）中。因此，细胞毒性蛋白共表达模式的这种全面的单细胞蛋白质组学评估证明了T细胞和NK细胞中与其分化阶段相关的专门细胞毒性程序。这种全面的细胞毒性分析可以识别与特定感染、自身免疫或肿瘤环境相关的细胞毒性潜力的不同模式。
The elimination of infected or tumor cells by direct lysis is a key T and NK cell effector function. T and NK cells can kill target cells by coordinated secretion of cytotoxic granules containing one or both pore-forming proteins, perforin and granulysin and combinations of granzyme (Gzm) family effector proteases (in humans: Gzm A, B, K, M and H). Understanding the pattern of expression of cytotoxic molecules and the relationship to different states of T and NK cells may have direct relevance for immune responses in autoimmunity, infectious disease and cancer. Approaches capable of simultaneously evaluating expression of multiple cytotoxic molecules with detailed information on T and NK differentiation state, however, remain limited. Here, we established a high dimensional mass cytometry approach to comprehensively interrogate single cell proteomic expression of cytotoxic programs and lymphocyte differentiation. This assay identified a coordinated expression pattern of cytotoxic molecules linked to CD8 T cell differentiation stages. Coordinated high expression of perforin, granulysin, Gzm A, Gzm B and Gzm M was associated with markers of late effector memory differentiation and expression of chemokine receptor CX3CR1. However, classical gating and dimensionality reduction approaches also identified other discordant patterns of cytotoxic molecule expression in CD8 T cells, including reduced perforin, but high Gzm A, Gzm K and Gzm M expression. When applied to non-CD8 T cells, this assay identified different patterns of cytotoxic molecule co-expression on CD56hi versus CD56dim defined NK cell developmental stages; in CD4 T cells, low expression of cytotoxic molecules was found mainly in TH1 phenotype cells, but not in Tregs or T follicular helper cells (TFH). Thus, this comprehensive, single cell, proteomic assessment of cytotoxic protein co-expression patterns demonstrates specialized cytotoxic programs in T cells and NK cells linked to their differentiation stages. Such comprehensive cytotoxic profiling may identify distinct patterns of cytotoxic potential relevant for specific infections, autoimmunity or tumor settings.
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