An Integrated Epigenomic and Transcriptomic Map of Mouse and Human aß T Cell Development

Author:

Chopp, Laura B

Gopalan, Vishaka

Ciucci, Thomas

Ruchinskas,Allison

Rae, Zachary

Lagarde, Manon

Gao, Yayi

Li, Caiyi

Bosticardo, Marita

Pala, Francesca

Livak, Ferenc

Kelly,Michael

Hannenhalli, Sridhar

Bosselut, Rémy
Author Address

Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Immunology Graduate Group, University of Pennsylvania Medical School, Philadelphia, PA, USA., Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Cancer Research Technology Program, Single Cell Analysis Facility, Frederick National Laboratory for Cancer Research, Bethesda, MD, USA., Laboratory of Genomic Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: bosselur@nih.gov.,

Abstract:

aß lineage T cells, most of which are CD4+ or CD8+ and recognize MHC I- or MHC II-presented antigens, are essential for immune responses and develop from CD4+CD8+ thymocytes. The absence of in vitro models and the heterogeneity of aß thymocytes have hampered analyses of their intrathymic differentiation. Here, combining single-cell RNA and ATAC (chromatin accessibility) sequencing, we identified mouse and human aß thymocyte developmental trajectories. We demonstrated asymmetric emergence of CD4+ and CD8+ lineages, matched differentiation programs of agonist-signaled cells to their MHC specificity, and identified correspondences between mouse and human transcriptomic and epigenomic patterns. Through computational analysis of single-cell data and binding sites for the CD4+-lineage transcription factor Thpok, we inferred transcriptional networks associated with CD4+- or CD8+-lineage differentiation, and with expression of Thpok or of the CD8+-lineage factor Runx3. Our findings provide insight into the mechanisms of CD4+ and CD8+ T cell differentiation and a foundation for mechanistic investigations of aß T cell development. Published by Elsevier Inc.

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