RT Journal Article
SR Electronic
T1 Suppression by human FOXP3<sup>+</sup> regulatory T cells requires FOXP3-TIP60 interactions
JF Science Immunology
JO Sci. Immunol.
FD American Association for the Advancement of Science
SP eaai9297
DO 10.1126/sciimmunol.aai9297
VO 2
IS 12
A1 Bin Dhuban, Khalid
A1 d’Hennezel, Eva
A1 Nagai, Yasuhiro
A1 Xiao, Yan
A1 Shao, Steven
A1 Istomine, Roman
A1 Alvarez, Fernando
A1 Ben-Shoshan, Moshe
A1 Ochs, Hans
A1 Mazer, Bruce
A1 Li, Bin
A1 Sekine, Chiyoko
A1 Berezov, Alan
A1 Hancock, Wayne
A1 Torgerson, Troy R.
A1 Greene, Mark I.
A1 Piccirillo, Ciriaco A.
YR 2017
UL http://immunology.sciencemag.org/content/2/12/eaai9297.abstract
AB Individuals with mutations in Foxp3 develop an autoimmune syndrome called immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX). However, the severity of IPEX varies depending on the specific Foxp3 mutation. Now, Bin Dhuban et al. find that the most common IPEX mutation, p.A384T, disrupts FOXP3 binding to the histone acetyltransferase TIP60 (KAT5), resulting in abrogated regulatory T (Treg) cell suppressive capacity, but maintained repression of proliferation and inflammatory cytokine production. Allosteric modifiers that help stabilize TIP60-FOXP3 interactions by inhibiting the autoacetylation of TIP60 molecules correct this disruption. These data suggest that targeting this interaction may be a therapeutic avenue in treating IPEX and other autoimmune and inflammatory diseases.CD4+FOXP3+ regulatory T (Treg) 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 Treg cells. We found that the p.A384T mutation abrogated the suppressive capacity of Treg cells while preserving FOXP3’s ability to repress inflammatory cytokine production. This selective functional impairment is partly due to a specific disruption of FOXP3A384T 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 Treg biology and provide a potential target for therapeutic manipulation of Treg activity.