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

Abstract

CD4FOXP3 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.

FoxP3 in Treg cell biology: a molecular and structural perspective

“…a). Our preclinical results have shown that the allosteric modification of TIP60 improves the FoxP3‐mediated transcriptional program in FoxP3A384T T reg cells, the therapeutic restoration of FoxP3–TIP60 interaction by this small molecule modifier promotes T reg cell function without directly affecting T effector cell responses, and enhances disease protection in mouse models of colitis and collagen‐induced arthritis .…”

Der p 1‐specific regulatory T‐cell response during house dust mite allergen immunotherapy

“…FOXP3 plays an essential role in the maintenance of immunological tolerance to self and innocuous foreign antigens . FOXP3 homodimers can mediate transcriptional regulation through direct binding to DNA, and FOXP3 has also been shown to interact with several molecular partners forming FOXP3/protein complexes that are required for several regulatory processes …”

Mechanisms of human FoxP3+ Treg cell development and function in health and disease

“…For example, acetylation of FoxP3 upon complexing with p300 allows it to evade proteasomal degradation, which constitutes a post‐translational mechanism of FoxP3 stability . Furthermore, we have recently shown that abrogating the FoxP3–Tat‐interacting protein 60 (TIP60) interaction, a defect caused by the germline foxp3 A384T IPEX mutation, relieves human T reg cell suppressive capacity while retaining major aspects of the T reg cell phenotype including the repression of proliferation and inflammatory cytokines . Restoring this interaction using a TIP60 allosteric modifier rescued FoxP3 functions and T reg cell suppressive capacity in vitro and in vivo .…”

“…R397W and I363V) or interactions with other proteins that aid in orchestrating the T reg transcriptional program (e.g. A384T) . Importantly, the presence of a mutation does not necessarily imply diminished FoxP3 protein expression levels (e.g.…”