Human epigenetic and transcriptional T cell differentiation atlas for identifying functional T cell-specific enhancers

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 th...

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Published in:	Immunity (Cambridge, Mass.) Mass.), 2022-03, Vol.55 (3), p.557-574.e7
Main Authors:	Giles, Josephine R., Manne, Sasikanth, Freilich, Elizabeth, Oldridge, Derek A., Baxter, Amy E., George, Sangeeth, Chen, Zeyu, Huang, Hua, Chilukuri, Lakshmi, Carberry, Mary, Giles, Lydia, Weng, Nan-Ping P., Young, Regina M., June, Carl H., Schuchter, Lynn M., Amaravadi, Ravi K., Xu, Xiaowei, Karakousis, Giorgos C., Mitchell, Tara C., Huang, Alexander C., Shi, Junwei, Wherry, E. John
Format:	Article
Language:	eng
Subjects:	CD8 T cell differentiation CD8-Positive T-Lymphocytes Cell Differentiation - genetics Chromatin - genetics Chromatin - metabolism CRISPR Epigenesis, Genetic epigenetic regulation epigenome engineering Epigenomics Humans Lymphocyte Activation - genetics
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Summary:	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. •RNA-seq and ATAC-seq atlas of 14 human T cell subsets from healthy donors•The atlas provides a reference map for interpreting signatures of T cells from 3 diseases•Prediction of cis-regulatory elements that control CD8 T cell subset gene expression•Validation of functional enhancers for CXCR3 and GZMB using CRISPRi Giles et al. generated an epigenomic T cell differentiation atlas from healthy human donor (HD) blood. This atlas was used to (1) identify transcriptional and epigenetic modules in human CD8 T cell differentiation, (2) interpret signatures of T cells from cancer and autoimmunity, and (3) predict and validate CD8 T cell enhancers.
ISSN:	1074-7613 1097-4180