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Multimodal single cell profiling identifies nclTECs and links chromatin remodeling to TEC differentiation and self-antigen expression modes [scATAC-seq]

ABSTRACT: Using single-cell profiling of the paediatric human thymus, we characterise the chromatin landscape and cell type heterogeneity of TECs and identify regulatory programs underlying thymic epithelial differentiation and tissue-restricted antigen expression. Based on differences in chromatin accessibility, we resolve three subpopulations within the previously reported mcTEC progenitor population, and show that differentiation towards mTEC(III) involves chromatin remodelling reminiscent of epidermal differentiation. Substantial differences in chromatin accessibility are observed across TEC populations at distal regulatory elements, which we hypothesise contribute to stochastic expression of tissue-restricted antigens. Our findings provide insight into mechanisms underlying immunodeficiencies, autoimmune diseases, and certain cancer types, and may inform therapies using engineered or transplanted thymic tissue to induce or enhance T-cell function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE318154 | GEO | 2026/07/17

REPOSITORIES: GEO

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Multimodal single cell profiling identifies nclTECs and links chromatin remodeling to TEC differentiation and self-antigen expression modes [scMultiome-seq]

Project description:Using single-cell profiling of the paediatric human thymus, we characterise the chromatin landscape and cell type heterogeneity of TECs and identify regulatory programs underlying thymic epithelial differentiation and tissue-restricted antigen expression. Based on differences in chromatin accessibility, we resolve three subpopulations within the previously reported mcTEC progenitor population, and show that differentiation towards mTEC(III) involves chromatin remodelling reminiscent of epidermal differentiation. Substantial differences in chromatin accessibility are observed across TEC populations at distal regulatory elements, which we hypothesise contribute to stochastic expression of tissue-restricted antigens. Our findings provide insight into mechanisms underlying immunodeficiencies, autoimmune diseases, and certain cancer types, and may inform therapies using engineered or transplanted thymic tissue to induce or enhance T-cell function.

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Project description:The crosstalk between thymocytes and thymic epithelial cells is critical for T cell development and establishment of central tolerance. Although the role of Autoimmune Regulator (Aire) gene in the induction of central tolerance is well known, the precise cellular and molecular mechanisms by which Aire controls the ectopic expression of tissue restricted antigens (TRAs) in medullary thymic epithelial cells (mTECS) remain unclear. In this study we performed a functional assay with fresh thymocytes dissociated from a normal mouse thymus co-cultured with a Mus musculus mTEC cell line - named 3.10 mTEC line - , in which we had previously knocked-down Aire gene by means of siRNA transfection. Agilent Mouse Gene Expression microarrays were used to determine the large scale transcriptional expression profiles of control and Aire-knockdown 3.10 mTECs co-cultured with thymocytes.

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