Suppression by human FOXP3+ regulatory T cells requires FOXP3-TIP60 interactions
Suppression by human FOXP3+ regulatory T cells requires FOXP3-TIP60 interactions
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DOI：
10.1126/sciimmunol.aai9297
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发表时间：
2017-06-01
影响因子：
24.8
通讯作者：
Piccirillo, Ciriaco A.
中科院分区：
文献类型：
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作者：
Bin Dhuban, Khalid;d'Hennezel, Eva;Piccirillo, Ciriaco A.
CD4(+)FOXP3（+）调节性T细胞（T-reg）是免疫耐受的关键介质，在免疫失调多内分泌性肠病x连锁综合征（IPEX）患者中，FOXP3突变导致其缺乏，导致严重的自身免疫。不同的FOXP3突变导致不同的疾病严重程度，反映了受影响残基在FOXP3蛋白完整性及其各种分子相互作用中的相对重要性。我们描述了最常见的IPEX突变p.A384T对患者来源的T-reg细胞的细胞和分子影响。我们发现p.A384T突变消除了T-reg细胞的抑制能力，同时保留了FOXP3抑制炎症细胞因子产生的能力。这种选择性功能损伤部分是由于FOXP3（A384T）与组蛋白乙酰转移酶tat相互作用蛋白60 (TIP60) （KAT5）结合的特异性破坏，可以使用增强FOXP3-TIP60相互作用的变弹性修饰剂来纠正。这些发现揭示了TIP60在foxp3驱动的T-reg生物学中的功能影响，并为治疗性操纵T-reg活性提供了潜在的靶点。
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.