The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance.
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.
1] Diabetes Center, University of California San Francisco, San Francisco, California, USA. [2] Department of Pediatrics, University of California San Francisco, San Francisco, California, USA.
Michael
M
Waterfield
Diabetes Center, University of California San Francisco, San Francisco, California, USA.
Imran S
IS
Khan
Diabetes Center, University of California San Francisco, San Francisco, California, USA.
Jessica T
JT
Cortez
Diabetes Center, University of California San Francisco, San Francisco, California, USA.
Una
U
Fan
Diabetes Center, University of California San Francisco, San Francisco, California, USA.
Todd
T
Metzger
Department of Microbiology & Immunology, University of California San Francisco, San Francisco, California, USA.
Alexandra
A
Greer
Diabetes Center, University of California San Francisco, San Francisco, California, USA.
Kayla
K
Fasano
Department of Liver Sciences, Division of Transplantation Immunology & Mucosal Biology, Institute of Liver Studies, King's College London, London, UK.
Marc
M
Martinez-Llordella
Department of Medicine, University of California San Francisco, San Francisco, California, USA.
Joshua L
JL
Pollack
Department of Medicine, University of California San Francisco, San Francisco, California, USA.
David J
DJ
Erle
Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Maureen
M
Su
1] Diabetes Center, University of California San Francisco, San Francisco, California, USA. [2] Department of Medicine, University of California San Francisco, San Francisco, California, USA.
Mark S
MS
Anderson
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D061167:Central Tolerance / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007108:Immune Tolerance; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D014162:Transfection; D020798:Two-Hybrid System Techniques; D000096927:AIRE Protein
D001324:Autoantigens; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000096927:AIRE Protein; C408904:Atf7ip protein, mouse; C489323:Mbd1 protein, mouse