Single-cell multiomic analysis of thymocyte development reveals drivers of CD4 T cell and CD8 T cell lineage commitment.
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| Abstract | The development of CD4 T cells and CD8 T cells in the thymus is critical to adaptive immunity and is widely studied as a model of lineage commitment. Recognition of self-peptide major histocompatibility complex (MHC) class I or II by the T cell antigen receptor (TCR) determines the CD8 or CD4 T cell lineage choice, respectively, but how distinct TCR signals drive transcriptional programs of lineage commitment remains largely unknown. Here we applied CITE-seq to measure RNA and surface proteins in thymocytes from wild-type and T cell lineage-restricted mice to generate a comprehensive timeline of cell states for each T cell lineage. These analyses identified a sequential process whereby all thymocytes initiate CD4 T cell lineage differentiation during a first wave of TCR signaling, followed by a second TCR signaling wave that coincides with CD8 T cell lineage specification. CITE-seq and pharmaceutical inhibition experiments implicated a TCR-calcineurin-NFAT-GATA3 axis in driving the CD4 T cell fate. Our data provide a resource for understanding cell fate decisions and implicate a sequential selection process in guiding lineage choice. |
| Year of Publication | 2023
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| Journal | Nature immunology
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| Date Published | 08/2023
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| ISSN | 1529-2916
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| DOI | 10.1038/s41590-023-01584-0
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| PubMed ID | 37580604
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