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

Publisher: Cell Press Country of Publication: United States NLM ID: 9432918 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4180 (Electronic) Linking ISSN: 10747613 NLM ISO Abbreviation: Immunity Subsets: MEDLINE

Publication: Cambridge, MA : Cell Press
Original Publication: Cambridge, Mass. : Cell Press, c1994-

Cell Differentiation/*immunology ; Cell Lineage/*immunology ; T-Lymphocyte Subsets/*immunology ; Thymocytes/*immunology; Animals ; Antigen Presentation/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Cell Differentiation/genetics ; Cell Lineage/genetics ; Epigenome ; Gene Expression Regulation ; Gene Regulatory Networks ; Histocompatibility Antigens/genetics ; Histocompatibility Antigens/immunology ; Histocompatibility Antigens/metabolism ; Humans ; Mice ; T-Lymphocyte Subsets/metabolism ; Thymocytes/metabolism ; Thymus Gland/immunology ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcriptome

αβ 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 αβ thymocytes have hampered analyses of their intrathymic differentiation. Here, combining single-cell RNA and ATAC (chromatin accessibility) sequencing, we identified mouse and human αβ 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 αβ T cell development.
Competing Interests: Declaration of Interests The authors declare no competing interests.
(Published by Elsevier Inc.)

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HHSN261200800001C United States CA NCI NIH HHS; HHSN261200800001E United States CA NCI NIH HHS; Z99 CA999999 United States ImNIH Intramural NIH HHS

Keywords: CD4 T cells; CD8 T cells; Gene regulatory networks; Human thymus; T cell development; Thpok; Transcriptional regulation; single-cell ATACseq; single-cell RNAseq; thymic selection

0 (Histocompatibility Antigens)
0 (Th-POK protein, mouse)
0 (Transcription Factors)

Date Created: 20201126 Date Completed: 20210521 Latest Revision: 20240615

20240615

PMC8641659

10.1016/j.immuni.2020.10.024

33242395