Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance

Yang, Siyoung; Fujikado, Noriyuki; Kolodin, Dmitriy; Benoist, Christophe; Mathis, Diane

doi:10.1126/science.aaa7017

Cited by 388 publications

(415 citation statements)

References 41 publications

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“…1B). Because it has been recently demonstrated that there are distinct Treg populations that are generated in an age-dependent manner and have different TCR repertoires (54), it might be possible that SATB1-dependent and SATB1-independent Treg cells are present. In addition to the decreased number, the suppressive functions of Treg cells were slightly impaired in the absence of SATB1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

SATB1 Plays a Critical Role in Establishment of Immune Tolerance

Kondo

Tanaka

Kuwabara

et al. 2016

The Journal of Immunology

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Special AT-rich sequence binding protein 1 (SATB1) is a genome organizer that is expressed by T cells. T cell development is severely impaired in SATB1 null mice; however, because SATB1 null mice die by 3 wk of age, the roles of SATB1 in T cell development have not been well clarified. In this study, we generated and analyzed SATB1 conditional knockout (cKO) mice, in which the SATB1 gene was deleted from all hematopoietic cells. T cell numbers were reduced in these mice, mainly because of a deficiency in positive selection at the CD4+CD8+ double-positive stage during T cell development in the thymus. We also found that SATB1 cKO mice developed autoimmune diseases within 16 wk after birth. In SATB1 cKO mice, the numbers of Foxp3+ regulatory T (Treg) cells were significantly reduced at 2 wk of age compared with wild-type littermates. Although the numbers gradually increased upon aging, Treg cells in SATB1 cKO mice were still less than those in wild-type littermates at adulthood. Suppressive functions of Treg cells, which play a major role in establishment of peripheral tolerance, were also affected in the absence of SATB1. In addition, negative selection during T cell development in the thymus was severely impaired in SATB1 deficient mice. These results suggest that SATB1 plays an essential role in establishment of immune tolerance.

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Section: Discussionmentioning

confidence: 99%

SATB1 Plays a Critical Role in Establishment of Immune Tolerance

Kondo

Tanaka

Kuwabara

et al. 2016

The Journal of Immunology

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“…[1][2][3][4][5] mTECs express membrane either proteins normally expressed in the thymus and proteins expressed in peripheral organs, called tissue-specific antigens (TSAs). The transcription factor autoimmune regulator (AIRE) gene (NM_000383.3), by promoting the ectopic expression of thousands of genes encoding TSAs in mTECs, plays a fundamental role in the tolerance process.…”

Section: Introductionmentioning

confidence: 99%

Expression and prognostic significance of the autoimmune regulator gene in breast cancer cells

et al. 2016

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The autoimmune regulator gene (AIRE) plays a fundamental role in tolerance by promoting the expression of tissue-specific antigens in medullary thymic epithelial cells (mTECs). Recently, AIRE expression was detected also in human keratinocytes and in tumors originating in stratified epithelia. Here, we tested whether AIRE is expressed in cancer cells. We analyzed AIRE expression in cancer cases from The Cancer Genome Atlas (TCGA) RNA-seq dataset and we found association with better outcome. AIRE protein expression was verified by immunohistochemistry in a cohort of 39 human breast cancer specimens and its prognostic relevance was confirmed in microarray-based gene expression data set NKI-295 and KM-Plotter. Both in the RNA-seq and gene expression datasets analyzed, AIRE expression was an independent strong prognostic factor for relapse-free survival (RFS), particularly in estrogen receptor-positive tumors. Enrichment of translation-related pathways was observed in AIRE-expressing tumors by Ingenuity Pathway Analysis and a significant increase of cells in G1 phase and activation of caspase cascades was induced by AIRE transfection in breast cancer luminal cell lines, suggesting that AIRE-induced over-translation of proteins lead to cycle arrest and apoptosis. These data are the first to identify AIRE expression in breast cancer and an association with prognosis.

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“…The Autoimmune Regulator ( AIRE) gene is the disease-causing gene [3,4]. AIRE acts as a transcriptional regulator and is almost exclusively expressed in the thymus [5] where it orchestrates the process of negative selection of self-reactive T cells and contributes to the development of regulatory T cells (Tregs) [6,7]. All patients present autoantibodies against autoantigens expressed in the affected tissue [8] and/or against immune mediators such as interferon-omega (ω) and interleukin (IL)-22 [9,10].…”

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confidence: 99%

Oral microbiota in autoimmune polyendocrine syndrome type 1

Bruserud

Siddiqui

Marthinussen

et al. 2018

Journal of Oral Microbiology

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Background: Autoimmune polyendocrine syndrome type-1 (APS-1) is a rare, childhood onset disease caused by mutations in the Autoimmune Regulator gene. The phenotypic expression is highly variable and includes disease manifestations in the oral cavity, including mucocutaneous candidiasis. Increasing evidence suggests a potential role of the skin, oral and gut microbiotas in the pathogenesis of autoimmunity. To date, no information exists regarding the oral microbiota in APS-1. Objective: To assess the bacterial microbiota of whole saliva in APS-1 patients by using high throughput sequencing. Design: Whole unstimulated saliva was collected from 10 APS-1 patients and 17 healthy controls and examined by high throughput sequencing of the hypervariable region V1-V2 of 16S rRNA using the 454 GS Junior system. Metastats (http://cbcb.umd.edu/software/metastats) was used to analyse the pyrosequencing reads. Results: A reduction in the total number of bacterial genera and species was detected in APS-1 compared to healthy controls. The proportion of the major phyla Firmicutes was higher (60% vs 41%, p = 0.002) and Bacteroidetes lower (15% vs 28%, p = 0.007) in APS-1 compared to healthy controls. On the genus level, Streptococcus and Gemella were prevalent in APS-1. Conclusion: Our findings indicate a significantly altered oral microbiota in APS-1.

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Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance

Cited by 388 publications

References 41 publications

SATB1 Plays a Critical Role in Establishment of Immune Tolerance

SATB1 Plays a Critical Role in Establishment of Immune Tolerance

Expression and prognostic significance of the autoimmune regulator gene in breast cancer cells

Oral microbiota in autoimmune polyendocrine syndrome type 1

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