CD29鉴定具有增加的细胞毒性潜能的产生IFN-γ的人CD8 + T细胞

StephenW

CD29 identifies IFN-γ–producing human CD8+ T cells with an increased cytotoxic potential
Benoît P. Nicolet, Aurélie Guislain, Floris P. J. van Alphen, Raquel Gomez-Eerland, Ton N. M. Schumacher, Maartje van den Biggelaar, and Monika C. Wolkers
PNAS March 24, 2020 117 (12) 6686-6696; first published March 11, 2020 https://doi.org/10.1073/pnas.1913940117
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    Edited by Anjana Rao, La Jolla Institute for Allergy and Immunology, La Jolla, CA, and approved February 12, 2020 (received for review August 12, 2019)

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Significance

Human CD8+ T cells can effectively kill target cells. However, not all CD8+ T cells are equally efficient herein. We developed a method to dissect the transcriptome and proteome of FACS-sorted cytokine-producing fixed human CD8+ T cells. We show that CD29 identifies IFN-γ–producing CD8+ T cells with high expression levels of cytotoxic molecules. Preselecting for CD29+ T cells potentiated the killing capacity of CD8+ T cell products. Reanalysis of published scRNA-seq data revealed a core signature of CD29+ T cells, which had a good predictive value for survival in melanoma patients. In conclusion, our study provides fundamental insights in the heterogeneity and functionality of human CD8+ T cells, which could help potentiate the efficacy of adoptive T cell therapies.
Abstract

Cytotoxic CD8+ T cells can effectively kill target cells by producing cytokines, chemokines, and granzymes. Expression of these effector molecules is however highly divergent, and tools that identify and preselect CD8+ T cells with a cytotoxic expression profile are lacking. Human CD8+ T cells can be divided into IFN-γ– and IL-2–producing cells. Unbiased transcriptomics and proteomics analysis on cytokine-producing fixed CD8+ T cells revealed that IL-2+ cells produce helper cytokines, and that IFN-γ+ cells produce cytotoxic molecules. IFN-γ+ T cells expressed the surface marker CD29 already prior to stimulation. CD29 also marked T cells with cytotoxic gene expression from different tissues in single-cell RNA-sequencing data. Notably, CD29+ T cells maintained the cytotoxic phenotype during cell culture, suggesting a stable phenotype. Preselecting CD29-expressing MART1 TCR-engineered T cells potentiated the killing of target cells. We therefore propose that CD29 expression can help evaluate and select for potent therapeutic T cell products.

StephenW

CD29鉴定具有增加的细胞毒性潜能的产生IFN-γ的人CD8 + T细胞
BenoîtP. Nicolet，AurélieGuislain，Floris P.J. van Alphen，Raquel Gomez-Eerland，Ton N.M.Schumacher，Maartje van den Biggelaar和Monika C.Wolkers
PNAS 2020年3月24日117（12）6686-6696;首次发布于2020年3月11日https://doi.org/10.1073/pnas.1913940117
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由加利福尼亚州拉霍亚拉荷亚过敏和免疫学研究所的Anjana Rao编辑，并于2020年2月12日批准（2019年8月12日接受审查）

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意义

人CD8 + T细胞可有效杀死靶细胞。但是，并不是所有的CD8 + T细胞在这里都同样有效。我们开发了一种方法来解剖FACS分选的产生细胞因子的固定人CD8 + T细胞的转录组和蛋白质组。我们显示CD29可以识别具有高表达水平的细胞毒性分子的IFN-γ产生CD8 + T细胞。预选CD29 + T细胞可增强CD8 + T细胞产物的杀伤能力。对已发表的scRNA-seq数据的重新分析揭示了CD29 + T细胞的核心特征，对于黑素瘤患者的生存具有良好的预测价值。总之，我们的研究为人类CD8 + T细胞的异质性和功能性提供了基本的见识，这可能有助于增强过继性T细胞疗法的疗效。
抽象

细胞毒性CD8 + T细胞可通过产生细胞因子，趋化因子和颗粒酶来有效杀死靶细胞。然而，这些效应分子的表达高度不同，并且缺乏鉴定和预选具有细胞毒性表达谱的CD8 + T细胞的工具。人类CD8 + T细胞可分为产生IFN-γ和IL-2的细胞。对产生细胞因子的固定CD8 + T细胞进行公正的转录组学和蛋白质组学分析表明，IL-2 +细胞产生辅助细胞因子，而IFN-γ+细胞产生细胞毒性分子。刺激之前，IFN-γ+ T细胞已经表达了表面标记CD29。 CD29还在单细胞RNA测序数据中用不同组织的细胞毒性基因表达标记了T细胞。值得注意的是，CD29 + T细胞在细胞培养过程中保持细胞毒性表型，表明其表型稳定。预选表达CD29的MART1 TCR工程改造的T细胞可增强靶细胞的杀伤力。因此，我们提出CD29表达可以帮助评估和选择有效的治疗性T细胞产物。