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Multimodal human thymic profiling reveals trajectories and cellular milieu for T agonist selection [CITE-seq]

ABSTRACT: To prevent autoimmunity, thymocytes expressing self-reactive T cell receptors (TCRs) are negatively selected, however, divergence into tolerogenic, agonist-selected lineages represent an alternative fate. As thymocyte development, selection, and lineage choices are dependent on spatial context and cell-to-cell interactions, we have performed Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) and spatial transcriptomics on paediatric human thymus. Thymocytes expressing markers of strong TCR signalling diverged from the conventional developmental trajectory prior to CD4+ lineage commitment, while markers of different agonist cell populations (CD8αα(I), CD8αα(II), T(agonist), Treg(diff) and Treg) exhibited variable timing of induction. Expression profiles of chemokines and co-stimulatory molecules, together with spatial localization, supported that dendritic cells, B cells, and stromal cells contribute to agonist selection, with different subsets influencing thymocytes at specific developmental stages within distinct spatial niches. Understanding factors influencing agonist T cells is needed to benefit from their immunoregulatory effects in clinical use.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207204 | GEO | 2023/02/01

REPOSITORIES: GEO

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Multimodal human thymic profiling reveals trajectories and cellular milieu for T agonist selection [Spatial transcriptomics]

Project description:To prevent autoimmunity, thymocytes expressing self-reactive T cell receptors (TCRs) are negatively selected, however, divergence into tolerogenic, agonist-selected lineages represent an alternative fate. As thymocyte development, selection, and lineage choices are dependent on spatial context and cell-to-cell interactions, we have performed Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) and spatial transcriptomics on paediatric human thymus. Thymocytes expressing markers of strong TCR signalling diverged from the conventional developmental trajectory prior to CD4+ lineage commitment, while markers of different agonist cell populations (CD8αα(I), CD8αα(II), T(agonist), Treg(diff) and Treg) exhibited variable timing of induction. Expression profiles of chemokines and co-stimulatory molecules, together with spatial localization, supported that dendritic cells, B cells, and stromal cells contribute to agonist selection, with different subsets influencing thymocytes at specific developmental stages within distinct spatial niches. Understanding factors influencing agonist T cells is needed to benefit from their immunoregulatory effects in clinical use.

2023-02-01 | GSE207205 | GEO

BCL6 is required for the thymic development of TCRαβ+CD8αα+ intraepithelial lymphocyte lineage

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Project description:Inhibitory proteins, such as programmed cell death protein 1 (PD-1), have been extensively studied in peripheral T cell responses to foreign, self, and neoantigens. Notably, these proteins are first expressed during T cell development in the thymus. Reports suggest that PD-1 limits regulatory T cell (Treg) development, but the mechanism by which PD-1 exerts this function remains unknown. The present study expands the evaluation of PD-1 and its ligands in the thymus, demonstrating that some of the highest expressers of PD-1 and PD-L1 are agonist selected cells. Surprisingly, we reveal a selective role for PD-1 in regulating the developmental niche only for Tregs as other agonist selected cell populations, such as natural killer T cells, remain unchanged. We also ruled out PD-1 as a regulator of proliferation or cell death of agonist selected Tregs and further demonstrated that PD-1 deficient Tregs have reduced TCR signaling. Unexpectedly, the data suggests that PD-1 deficient thymocytes produce elevated levels of IL-2, a Treg niche limiting cytokine. Collectively, these data suggest a novel role for PD-1 in regulating IL-2 production and the concurrent agonist selection of thymic Tregs. This observation has implications for the use of checkpoint blockade in the context of cancer and infection.

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Single-cell transcriptional profiling identifies a spectrum of unconventional intraepithelial T lineage cells in human cord blood

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Multimodal human thymic profiling reveals trajectories and cellular milieu for T agonist selection [Spatial transcriptomics]

Project description:Multimodal human thymic profiling reveals trajectories and cellular milieu for T agonist selection [Spatial transcriptomics]

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

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Notch signaling is required for induction of an innate T cell development program in human thymus

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Single-cell transcriptional profiling identifies a spectrum of unconventional intraepithelial T lineage cells in human cord blood [scRNA-Seq]

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