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Nat Immunol ; 24(9): 1579-1590, 2023 09.
Article in English | MEDLINE | ID: mdl-37580604

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.


Subject(s)
CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Mice , Animals , Cell Lineage , Thymocytes , Multiomics , Mice, Transgenic , Cell Differentiation , Receptors, Antigen, T-Cell/metabolism , Thymus Gland , Histocompatibility Antigens Class I , CD4 Antigens
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