Aire suppresses CTLA-4 expression from thymic stroma to control autoimmunity
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ABSTRACT:
PROVIDER: PRJNA648393 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12318307_1.fastq.gz | Fastqsanger.gz | |||
| SRR12318307_2.fastq.gz | Fastqsanger.gz |
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Project description:We show that thymic epithelial cells in the medulla (mTECs) that present self-antigens (self-Ags) to developing thymocytes for establishing immunological self-tolerance also express CTLA-4 if Aire, loss of which is responsible for the hereditary autoimmunity, is nonfunctional. Upon binding with its ligand, CD80 and CD86, expressed on thymic DCs, CTLA-4/ligand complex was internalized by Aire-deficient mTECs. This attenuated the ability of DCs to provide costimulatory signals and to present self-Ags, resulting in the reduced production of Tregs.
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Project description:The deficiency of Aire, a transcriptional regulator whose defect results in the development of autoimmunity, is associated with reduced expression of tissue-restricted self-Ags (TRAs) in medullary thymic epithelial cells (mTECs). Although the mechanisms underlying Aire-dependent expression of TRAs need to be explored, the physical identification of the target(s) of Aire has been hampered by the low and promiscuous expression of TRAs. We have tackled this issue by engineering mice with augmented Aire expression. Integration of the transcriptomic data from Aire-augmented and Aire-deficient mTECs revealed that a large proportion of so-called Aire-dependent genes, including those of TRAs, may not be direct transcriptional targets downstream of Aire. Rather, Aire induces TRA expression indirectly through controlling the heterogeneity of mTECs, as revealed by single-cell analyses. In contrast, Ccl25 emerged as a canonical target of Aire, and we verified this both in vitro and in vivo. Our approach has illuminated the Aire?s primary targets while distinguishing them from the secondary targets.
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Project description:The zinc-finger transcription factor Ikaros (Ikzf1) modulates key gene expression programs important for hematopoietic development, and coding mutations in IKZF1 are found in patients with immunodeficiency, leukemia, and autoimmunity. While Ikaros has a well-established function in hematopoiesis, its role in other cell types is less well defined. Here, we uncover new functions for Ikaros in thymic epithelial lineage development and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both Autoimmune Regulator positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity and its deletion results in a dramatic expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function, and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.
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Project description:Aire in medullary thymic epithelial cells plays an essential role in the negative selection through expression of broad arrays of tissue-restricted antigens. We asked whether Aire could also activate the expression of tissue-restricted antigens in cortical thymic epithelial cells. We established a semi-knockin strain of NOD-background mice expressing Aire under control of the promoter of β5t, a thymoproteasome expressed exclusively in the cortex. We extracted RNA from cortical thymic epithelial cells ectopically expressing Aire and hybridization was performed on Affymetrix. microarrays.
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Project description:The zinc-finger transcription factor Ikaros (Ikzf1) modulates key gene expression programs important for hematopoietic development, and coding mutations in IKZF1 are found in patients with immunodeficiency, leukemia, and autoimmunity. While Ikaros has a well-established function in hematopoiesis, its role in other cell types is less well defined. Here, we uncover new functions for Ikaros in thymic epithelial lineage development and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both Autoimmune Regulator positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity and its deletion results in a dramatic expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function, and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.
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Project description:The zinc-finger transcription factor Ikaros (Ikzf1) modulates key gene expression programs important for hematopoietic development, and coding mutations in IKZF1 are found in patients with immunodeficiency, leukemia, and autoimmunity. While Ikaros has a well-established function in hematopoiesis, its role in other cell types is less well defined. Here, we uncover new functions for Ikaros in thymic epithelial lineage development and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both Autoimmune Regulator positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity and its deletion results in a dramatic expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function, and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.
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Project description:The zinc-finger transcription factor Ikaros (Ikzf1) modulates key gene expression programs important for hematopoietic development, and coding mutations in IKZF1 are found in patients with immunodeficiency, leukemia, and autoimmunity. While Ikaros has a well-established function in hematopoiesis, its role in other cell types is less well defined. Here, we uncover new functions for Ikaros in thymic epithelial lineage development and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both Autoimmune Regulator positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity and its deletion results in a dramatic expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function, and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.
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Project description:Aire in medullary thymic epithelial cells plays an essential role in the negative selection through expression of broad arrays of tissue-restricted antigens. We asked whether Aire could also activate the expression of tissue-restricted antigens in cortical thymic epithelial cells.
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Project description:Promiscuous gene expression (pGE) of numerous self-antigens in thymic epithelial cells (TEC) enables the elimination of self-reactive T cells. The autoimmune regulator (Aire) is the only known molecular determinant driving pGE in the thymus but the existence of Aire-independent mechanisms has been inferred. Here, we analyzed the poly(A)+ transcriptome of TEC populations by RNA-sequencing (RNA-seq) in order to reveal differential features of Aire-induced vs. –independent pGE. We report an unanticipated effect of Aire deletion on the proliferation and differentiation of cortical TEC. Moreover, the RNA-seq data reveal the breath of Aire-induced and –independent pGE in medullary TEC (mTEC) subsets and the extent of thymic peripheral tissue representation. The results suggest that Aire-induced promiscuously expressed transcripts affect several functions with far reaching biological consequences in mTEC. High-throughput characterization of TEC transcriptomes will enable progress in understanding TEC biology and the establishment of self-tolerance. The mRNA profiles of cTEC, mTEClo and mTEChi from 6-8 week-old wild type (WT) and Aire-/- (KO) mice were generated by RNA-sequencing using Illumina HiSeq2000.
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Project description:TEC (B6 vs Aire KO). Thymic epithelial cells from B6 strain and AIRE KO are compared.
2007-12-01 | E-GEOD-2515 | biostudies-arrayexpress