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

Khalid Bin Dhuban; Eva d'Hennezel; Yasuhiro Nagai; Yan Xiao; Steven Shao; Roman Istomine; Fernando Alvarez; Moshe Ben-Shoshan; Hans Ochs; Bruce Mazer; Bin Li; Chiyoko Sekine; Alan Berezov; Wayne Hancock; Troy R Torgerson; Mark I Greene; Ciriaco A Piccirillo

doi:10.1126/sciimmunol.aai9297

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

Sci Immunol. 2017 Jun 16;2(12):eaai9297. doi: 10.1126/sciimmunol.aai9297.

Authors

Khalid Bin Dhuban^{1

2}, Eva d'Hennezel¹, Yasuhiro Nagai³, Yan Xiao³, Steven Shao^{1

2}, Roman Istomine^{1

2}, Fernando Alvarez^{1

2}, Moshe Ben-Shoshan⁴, Hans Ochs⁵, Bruce Mazer^{4

6}, Bin Li³, Chiyoko Sekine, Alan Berezov³, Wayne Hancock³, Troy R Torgerson⁴, Mark I Greene³, Ciriaco A Piccirillo^{7

2

6

8}

Affiliations

¹ Department of Microbiology and Immunology, McGill University and Research Institute of McGill University Health Centre, Montréal, Québec H3A 2B4, Canada.
² Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of McGill University Health Centre, Montréal, Québec H4A 3J1, Canada.
³ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-6082, USA.
⁴ Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, McGill University Health Center, Montréal, Québec H3H 1P3, Canada.
⁵ Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98101-1304, USA.
⁶ FOCiS Centre of Excellence in Translational Immunology (CETI), Montréal, Québec H4A 3J1, Canada.
⁷ Department of Microbiology and Immunology, McGill University and Research Institute of McGill University Health Centre, Montréal, Québec H3A 2B4, Canada. ciro.piccirillo@mcgill.ca.
⁸ Division of Allergy and Clinical Immunology, Department of Medicine, McGill University and McGill University Health Centre, Montreal, Quebec, Canada.

PMID: 28783662
DOI: 10.1126/sciimmunol.aai9297

Abstract

CD4⁺FOXP3⁺ regulatory T (T_reg) cells are critical mediators of immune tolerance, and their deficiency owing to FOXP3 mutations in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) patients results in severe autoimmunity. Different FOXP3 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_reg cells. We found that the p.A384T mutation abrogated the suppressive capacity of T_reg cells while preserving FOXP3's ability to repress inflammatory cytokine production. This selective functional impairment is partly due to a specific disruption of FOXP3^A384T 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_reg biology and provide a potential target for therapeutic manipulation of T_reg activity.