The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance

The transcriptional regulator Aire is required for central tolerance, but how it manages to target tissue-specific genes is unclear. Anderson and colleagues show that Aire achieves such targeting by coopting the ATF7ip-MBD1 repressor complex. The maintenance of immunological tolerance requires the d...

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Published inNature immunology Vol. 15; no. 3; pp. 258 - 265
Main Authors Waterfield, Michael, Khan, Imran S, Cortez, Jessica T, Fan, Una, Metzger, Todd, Greer, Alexandra, Fasano, Kayla, Martinez-Llordella, Marc, Pollack, Joshua L, Erle, David J, Su, Maureen, Anderson, Mark S
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.03.2014
Nature Publishing Group
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Online AccessGet full text
ISSN1529-2908
1529-2916
1529-2916
DOI10.1038/ni.2820

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Abstract The transcriptional regulator Aire is required for central tolerance, but how it manages to target tissue-specific genes is unclear. Anderson and colleagues show that Aire achieves such targeting by coopting the ATF7ip-MBD1 repressor complex. The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1 −/− mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance.
AbstractList The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1(-/-) mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance.
The transcriptional regulator Aire is required for central tolerance, but how it manages to target tissue-specific genes is unclear. Anderson and colleagues show that Aire achieves such targeting by coopting the ATF7ip-MBD1 repressor complex. The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1 −/− mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance.
The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1(-/-) mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance.The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1(-/-) mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance.
The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, [Mbd1.sup.-/-] mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance.
The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1 super(-/-) mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance.
Audience Academic
Author Metzger, Todd
Fasano, Kayla
Erle, David J
Greer, Alexandra
Cortez, Jessica T
Khan, Imran S
Martinez-Llordella, Marc
Pollack, Joshua L
Anderson, Mark S
Su, Maureen
Fan, Una
Waterfield, Michael
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/24464130$$D View this record in MEDLINE/PubMed
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Snippet The transcriptional regulator Aire is required for central tolerance, but how it manages to target tissue-specific genes is unclear. Anderson and colleagues...
The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific...
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SubjectTerms 13
13/1
13/105
13/109
13/31
13/44
13/51
13/89
631/250/38
AIRE Protein
Animals
Autoantigens - immunology
Biomedicine
Central Tolerance - genetics
Central Tolerance - immunology
DNA-Binding Proteins - genetics
DNA-Binding Proteins - immunology
Flow Cytometry
Gene Expression Regulation - immunology
HEK293 Cells
Humans
Immune system
Immune Tolerance
Immunoblotting
Immunology
Immunoprecipitation
Infectious Diseases
Mice
Mice, Inbred C57BL
Mice, Knockout
Oligonucleotide Array Sequence Analysis
Physiological research
Properties
Protein Binding
Repressor Proteins - genetics
Repressor Proteins - immunology
Reverse Transcriptase Polymerase Chain Reaction
Transcription factors
Transcription Factors - genetics
Transcription Factors - immunology
Transfection
Two-Hybrid System Techniques
Title The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance
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