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Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion

嵌合抗原受体 生物 下调和上调 转录因子 免疫学 染色质 细胞生物学 细胞疗法 T细胞 受体 CD8型 免疫系统 自身免疫 干细胞 遗传学 基因
作者
Caroline Lamarche,Kirsten Ward-Hartstonge,Tian Mi,David T. S. Lin,Qing Huang,Andrew Brown,Karlie Edwards,Gherman Novakovsky,Christopher N. Qi,Michael S. Kobor,Caitlin C. Zebley,Evan W. Weber,Crystal L. Mackall,Megan K. Levings
出处
期刊:Proceedings of the National Academy of Sciences of the United States of America [Proceedings of the National Academy of Sciences]
卷期号:120 (14) 被引量:2
标识
DOI:10.1073/pnas.2219086120
摘要

Regulatory T cell (Treg) therapy is a promising approach to improve outcomes in transplantation and autoimmunity. In conventional T cell therapy, chronic stimulation can result in poor in vivo function, a phenomenon termed exhaustion. Whether or not Tregs are also susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. To "benchmark" exhaustion in human Tregs, we used a method known to induce exhaustion in conventional T cells: expression of a tonic-signaling chimeric antigen receptor (TS-CAR). We found that TS-CAR-expressing Tregs rapidly acquired a phenotype that resembled exhaustion and had major changes in their transcriptome, metabolism, and epigenome. Similar to conventional T cells, TS-CAR Tregs upregulated expression of inhibitory receptors and transcription factors such as PD-1, TIM3, TOX and BLIMP1, and displayed a global increase in chromatin accessibility-enriched AP-1 family transcription factor binding sites. However, they also displayed Treg-specific changes such as high expression of 4-1BB, LAP, and GARP. DNA methylation analysis and comparison to a CD8+ T cell-based multipotency index showed that Tregs naturally exist in a relatively differentiated state, with further TS-CAR-induced changes. Functionally, TS-CAR Tregs remained stable and suppressive in vitro but were nonfunctional in vivo, as tested in a model of xenogeneic graft-versus-host disease. These data are the first comprehensive investigation of exhaustion in Tregs and reveal key similarities and differences with exhausted conventional T cells. The finding that human Tregs are susceptible to chronic stimulation-driven dysfunction has important implications for the design of CAR Treg adoptive immunotherapy strategies.
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