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bioRxiv · 10.1101/2021.07.12.452119

Single-cell multi-omic analysis of thymocyte development reveals NFAT as adriver of CD4/CD8 lineage commitment

Steier, Z.·McIntyre, L. L.·Lutes, L. K.·Huang, T.-S.·Robey, E. A.·Yosef, N.·Streets, A.
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Abstract

The development of CD4 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-MHCI/II by the T cell antigen receptor (TCR) determines the lineage choice, but how distinct TCR signals drive transcriptional programs of lineage commitment remains largely unknown. We applied CITE-seq to measure RNA and surface proteins in thymocytes from wild-type and lineage-restricted mice to generate a comprehensive timeline of cell state for each lineage. These analyses revealed a sequential process whereby all thymocytes initiate CD4 lineage differentiation during an initial wave of TCR signaling, followed by a second TCR signaling wave that coincides with CD8 lineage specification. CITE-seq and pharmaceutical inhibition experiments implicate a TCR/calcineurin/NFAT/GATA3 axis in driving the CD4 fate. Overall, our data suggest that multiple redundant mechanisms contribute to the accuracy and efficiency of the lineage choice.

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Steier, Z., McIntyre, L. L., Lutes, L. K., Huang, T.-S., Robey, E. A., Yosef, N., Streets, A.. 2021-07-13. Single-cell multi-omic analysis of thymocyte development reveals NFAT as adriver of CD4/CD8 lineage commitment. https://doi.org/10.1101/2021.07.12.452119

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