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

Michael Waterfield, Imran S Khan, Jessica T Cortez, Una Fan, Todd Metzger, Alexandra Greer, Kayla Fasano, Marc Martinez-Llordella, Joshua L Pollack, David J Erle, Maureen Su, Mark S Anderson

Nature immunology 2014 Mar

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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.

Citation

Michael Waterfield, Imran S Khan, Jessica T Cortez, Una Fan, Todd Metzger, Alexandra Greer, Kayla Fasano, Marc Martinez-Llordella, Joshua L Pollack, David J Erle, Maureen Su, Mark S Anderson. The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. Nature immunology. 2014 Mar;15(3):258-65