期刊
IMMUNITY
卷 55, 期 3, 页码 557-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2022.02.004
关键词
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类别
资金
- Cancer Research Institute-Mark Foundation Fellowship
- NIH [CA234842, CA230157, AI155577, AI115712, AI117950, AI108545, AI082630, CA210944, U19AI149680]
- NHLBI [1R38HL143613]
- Tara Miller Award
- Parker Institute Bridge Scholar Award
- Parker Institute for Cancer Immunotherapy
- Allen Institute for Immunology
- Stand up to Cancer
- Penn Center for AIDS Research/Human Immunology Core [P30-AI045008/P30-CA016520]
- [P50-CA174523]
- [T32 CA009140]
This study generated an epigenetic and transcriptional atlas of T cell differentiation from healthy humans and applied it to explore disease-specific biology. The study identified molecular regulations of gene expression and chromatin accessibility during T cell differentiation and provided insights into disease biology through three research settings. The study also successfully predicted genome-wide cis-regulatory elements and validated the approach for functional annotation of key effector genes, demonstrating the potential of identifying targets for non-coding cellular engineering.
The clinical benefit of T cell immunotherapies remains limited by incomplete understanding of T cell differentiation and dysfunction. We generated an epigenetic and transcriptional atlas of T cell differentiation from healthy humans that included exhausted CD8 T cells and applied this resource in three ways. First, we identified modules of gene expression and chromatin accessibility, revealing molecular coordination of differentiation after activation and between central memory and effector memory. Second, we applied this healthy molecular framework to three settings-a neoadjuvant anti-PD1 melanoma trial, a basal cell carcinoma scATAC-seq dataset, and autoimmune disease-associated SNPs-yielding insights into disease specific biology. Third, we predicted genome-wide cis-regulatory elements and validated this approach for key effector genes using CRISPR interference, providing functional annotation and demonstrating the ability to identify targets for non-coding cellular engineering. These studies define epigenetic and transcriptional regulation of human T cells and illustrate the utility of interrogating disease in the context of a healthy T cell atlas.
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