Single-cell multiomic analysis of thymocyte development reveals drivers of CD4(+) T cell and CD8(+) T cell lineage commitment

Streets, Yosef, Robey and colleagues use multiomics analysis to generate a comprehensive timeline of the CD4(+) and CD8(+) T cell lineage commitment and identify sequential waves of TCR signaling that first initiate CD4(+) T cell lineage differentiation and then CD8(+) T cells lineage specification. 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.

Automated summary

Streets, Yosef, Robey and colleagues used multiomics analysis to establish a comprehensive timeline of the development of CD4(+) and CD8(+) T cells lineage commitment. They identified sequential waves of TCR signaling that initiate CD4(+) T cell lineage differentiation followed by CD8(+) T cell lineage specification. Their findings provide valuable insights into cell fate decisions and suggest a sequential selection process in guiding lineage choice.