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

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-MHCI or MHCII by the T cell antigen receptor (TCR) determines the CD8+ T cell 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 state for each T cell lineage. These analyses identified a sequential process whereby all thymocytes initiate CD4+ T cell lineage differentiation during an initial 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 multiple redundant mechanisms in guiding lineage choice.

ORGANISM(S): Mus musculus

PROVIDER: GSE186078 | GEO | 2023/06/30

REPOSITORIES: GEO

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HDAC3 restrains cytokine signaling during thymocyte development for the generation of CD4 T cells (RNA-Seq)

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HDAC3 restrains cytokine signaling during thymocyte development for the generation of CD4 T cells (ChIP-Seq)

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2015-12-19 | E-GEOD-73849 | biostudies-arrayexpress

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Project description:CD4 and CD8 identify helper and cytotoxic T cell lineages, and serve as co-receptors for MHC-restricted TCR recognition. Despite decades of investigation, questions remain about how TCR specificity and co-receptor gene expression are matched during T cell repertoire selection. Here we address the order and logic of CD4/CD8 lineage choice and differentiation by scRNA-seq. Maturation, activation, and lineage specification emerged as principle components, in this order. Co-receptor gene expression uncovered waves of Cd4+Cd8a+, Cd4+Cd8a- and Cd4-Cd8a+ selection intermediates and revealed gene expression programs associated with each pattern, including TCR- and cytokine signaling genes, lineage markers and transcription factors. While in the unperturbed thymus early Cd4+Cd8a+ selection intermediates were followed first by CD4-like Cd4+Cd8a- and later by CD8-like Cd4-Cd8a+ selection intermediates, the order of co-receptor gene expression was not inherently fixed. These data provide a benchmark for models of CD4/CD8 lineage choice, and a rich resource for interrogating T cell differentiation.

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2010-06-10 | E-GEOD-2262 | biostudies-arrayexpress

Innate-like T cell subset commitment in the murine thymus is independent of TCR characteristics and occurs during proliferation

Project description:we compare the TCR repertoires of MAIT1 and MAIT17 cells from the mouse thymus using 5’ scRNAseq and scTCRseq of MR1:5-OP-RU tetramer positive thymocytes. A thorough analysis of TCR features between MAIT sub-populations did not show any difference between the repertoires of MAIT1 and MAIT17 subsets. Quantitative simulation of clonotype distributions of MAIT1 and MAIT17 cells allowed us to investigate the role of TCR characteristics in MAIT fate choice, and to pinpoint the stage at which lineage commitment occurs. Our results indicate that the TCR characteristics are not instructive in MAIT lineage choice and that MAIT1/17 commitment takes place during MAIT cell proliferation in the thymus. Finally, we performed analogous analysis of a published scRNA-seq and scTCR-seq dataset of iNKT from mouse thymus and demonstrated that our conclusions are also relevant for iNKT1 vs iNKT17 fate commitment.

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Gene expression profile of Dicer knockout in mouse DP thymocytes

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2015-01-28 | E-GEOD-57511 | biostudies-arrayexpress

Genome-wide maps of SATB1 bound regions in thymocytes and peripheral CD4+ T lymphocytes.

Project description:T-cell receptor (TCR) signaling by MHC class-I and -II induces thymocytes to acquire cytotoxic and helper fates via induction of Runx3 or and ThPOK transcription factors, respectively. The mechanisms by The mechanisms by which TCR signaling is translated into transcriptional programs for each cell fate remain elusive. It remains elusivewhich how TCR signaling is translated into transcriptional programs for each cell fate remain elusive. We show that a genome organizer, SATB1, activates genes for lineage-specifying factors, including ThPOK, Runx3, CD4, CD8 and Treg factor Foxp3, and Treg factor Foxp3, and CD4, and /CD8, in post-selection thymocytes. Indeed, SATBatb1-deficient thymocytes are partially redirected into inappropriate T lineages after both MHC class-I and -II mediated selection, and fail to generate Treg subset. Despite its essential role in initiating regulatory regions activity in TCR signaled thymocytes. SATBatb1 is becomes dispensable for maintaining ThPOK in CD4+ T cells. Collectively, our findings demonstrate that SATBatb1 shapes the primary T-cell pool by initially directing lineage-specific transcriptional programs in the thymus.

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