Suppression by human FOXP3 + regulatory T cells requires FOXP3-TIP60 interactions

• Published in: Science immunology 2017-06, Vol.2 (12)
• Main Authors: Bin Dhuban, Khalid, d'Hennezel, Eva, Nagai, Yasuhiro, Xiao, Yan, Shao, Steven, Istomine, Roman, Alvarez, Fernando, Ben-Shoshan, Moshe, Ochs, Hans, Mazer, Bruce, Li, Bin, Sekine, Chiyoko, Berezov, Alan, Hancock, Wayne, Torgerson, Troy R, Greene, Mark I, Piccirillo, Ciriaco A
• Format: Article
• Language: English
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.aai9297

CD4 FOXP3 regulatory T (T ) cells are critical mediators of immune tolerance, and their deficiency owing to mutations in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) patients results in severe autoimmunity. Different mutations result in a wide range of disease severity, reflecting the relative importance of the affected residues in the integrity of the FOXP3 protein and its various molecular interactions. We characterized the cellular and molecular impact of the most common IPEX mutation, p.A384T, on patient-derived T cells. We found that the p.A384T mutation abrogated the suppressive capacity of T cells while preserving FOXP3's ability to repress inflammatory cytokine production. This selective functional impairment is partly due to a specific disruption of FOXP3 binding to the histone acetyltransferase Tat-interacting protein 60 (TIP60) (KAT5) and can be corrected using allosteric modifiers that enhance FOXP3-TIP60 interaction. These findings reveal the functional impact of TIP60 in FOXP3-driven T biology and provide a potential target for therapeutic manipulation of T activity.