Research ArticleAUTOIMMUNITY

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

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Science Immunology  16 Jun 2017:
Vol. 2, Issue 12, eaai9297
DOI: 10.1126/sciimmunol.aai9297

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TIPing the balance of autoimmunity

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.

Abstract

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.

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