Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells

Brennecke, Philip; Reyes, Alejandro; Pinto, Sheena; Rattay, Kristin; Nguyen, Michelle; Küchler, Rita; Huber, Wolfgang; Kyewski, Bruno; Steinmetz, Lars M.

doi:10.1038/ni.3246

Cited by 131 publications

(161 citation statements)

References 49 publications

(102 reference statements)

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“…Indeed, central self-tolerance depends on promiscuous gene expression by medullary thymic epithelial cells that collectively express almost all protein-coding genes (67,68). Remarkably, this promiscuous gene expression follows a mosaic pattern: individual medullary thymic epithelial cells promiscuously express a limited number of genes, but at a high level (67,69). A mosaic pattern of highly expressed genes may be instrumental in increasing the breadth of the MAP repertoire that can thereby induce central self-tolerance.…”

Section: Discussionmentioning

confidence: 99%

MHC class I–associated peptides derive from selective regions of the human genome

Pearson¹,

Daouda²,

Granados³

et al. 2016

Journal of Clinical Investigation

179

218

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Section: Discussionmentioning

confidence: 99%

MHC class I–associated peptides derive from selective regions of the human genome

Pearson¹,

Daouda²,

Granados³

et al. 2016

Journal of Clinical Investigation

179

218

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“…Still, the expression of Aire 25 and Fezf 24 was normal in p53cKO mTECs. Because mTECs express clusters of TRAs at a single-cell level, 3,30 the reduction in TRAs might alternatively reflect an underrepresentation of certain mTEC subsets in mutant thymus.…”

Section: Discussionmentioning

confidence: 99%

Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice

Rodrigues

Ribeiro

Perrod³

et al. 2017

Blood

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Key points:• TEC-intrinsic ablation of p53 predominantly affects medullary TECs, altering their RANK-driven differentiation and transcriptome.• Loss of p53 in TECs couples disrupted thymopoiesis to altered T-cell homeostasis and tolerance Thymic epithelial cells (TECs) provide crucial microenvironments for T-cell development and tolerance induction. As the regular function of the thymus declines with age, it is of fundamental and clinical relevance to decipher new determinants that control TEC homeostasis in vivo. Beyond its recognized tumor suppressive function, p53 controls several immunoregulatory pathways. To study the cell-autonomous role of p53 in thymic epithelium functioning, we developed and analyzed mice with conditional inactivation of Trp53 in TECs (p53cKO). We report that loss of p53 primarily disrupts the integrity of medullary TEC (mTEC) niche, a defect that spreads to the adult cortical TEC compartment. Mechanistically, we found that p53 controls specific and broad programs of mTEC differentiation. Apart from restraining the expression and responsiveness of the receptor activator of NF-kB (RANK), which is central for mTEC differentiation, deficiency of p53 in TECs altered multiple functional modules of the mTEC transcriptome, including tissuerestricted antigen expression. As a result, p53cKO mice presented premature defects in mTEC-dependent regulatory T-cell differentiation and thymocyte maturation, which progressed to a failure in regular and regenerative thymopoiesis and peripheral Tcell homeostasis in the adulthood. Lastly, peripheral signs of altered immunological tolerance unfold in mutant mice and in immunodeficient mice that received p53cKO-derived thymocytes. Our findings position p53 as a novel molecular determinant of thymic epithelium function throughout life.Version: Postprint (identical content as published paper) This is a self-archived document from i3S -Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 IntroductionWithin the thymus, thymic epithelial cells (TECs) orchestrate the development of functionally diverse and self-tolerant T cells. 1 Importantly, impaired TEC functions arise with aging, cytoablative regimens and infection, which compromise T-cell responses to pathogens, and vaccination in the elderly, and patients undergoing bone marrow transplantation (BMT) or chemotherapy. Equally, failures in TEC-mediated tolerance induction lead to autoimmunity. 2 Hence, the identification of novel regulators of TEC homeostasis is crucial to comprehend the foundations of immunity and to intervene medically in disorders linked to a dysfunctional thymus.Cortical TECs (cTECs) and medullary TECs (mTECs) define 2 functionally distinct microenvironments, which differentiate from bipotent TEC progenitors. 1 Whereas cTECs drive T-cell lineage specification and positive selection, mTECs promote the maturation of positively selected thymocytes, regulatory T-c...

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“…Single-cell sequencing technologies have identified the complex heterogeneities and divergences of cell phenotype and function. [170][171][172] Advances in genomics, transcriptomics, proteomics, metabolomics, interactomics, phenomics have illustrated the complex networks of immune cells and molecules in the settings of health and diseases. 173 Development of new mouse strains such as the mouse strain lacking iNKT cells 174 and new disease models such as the mice with myeloid-cell-specific deletion of A20 as a new model of rheumatoid arthritis 175 have provided useful tools for immunological studies.…”

Section: Discussionmentioning

confidence: 99%

Cellular and molecular regulation of innate inflammatory responses

2016

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Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells

Cited by 131 publications

References 49 publications

MHC class I–associated peptides derive from selective regions of the human genome

MHC class I–associated peptides derive from selective regions of the human genome

Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice

Cellular and molecular regulation of innate inflammatory responses

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