Iranian Journal of Basic Medical Sciences

Iranian Journal of Basic Medical Sciences

Cutaneous autoimmunity in immunodeficiency: Central role of FOXP3 and regulatory T-cell dysfunction

Document Type : Review Article

Authors
Suzhou Wuzhong People’s Hospital, Wuzhong District Dermatology Hospital, Suzhou, Jiangsu 215128, China
10.22038/ijbms.2026.96279.20761
Abstract
Regulatory T cells (Tregs), orchestrated by the master transcription factor FOXP3, are pivotal for maintaining immune tolerance in the skin, a complex barrier tissue constantly exposed to environmental antigens and commensal microbiota. Dysfunction of the FOXP3–Treg axis underlies a spectrum of primary immunodeficiencies (PIDs) characterized by prominent cutaneous autoimmunity, including eczematous dermatitis, erythroderma, psoriasiform lesions, and alopecia. This review synthesizes the specialized cutaneous immune microenvironment integrating keratinocytes, dendritic cells, and tissue-resident Tregs and delineates the transcriptional, epigenetic, and signaling mechanisms governing FOXP3 stability and Treg function. Particular emphasis is placed on Treg plasticity, whereby inflammatory cues drive conversion to pro-inflammatory ex-Tregs, exacerbating Th17/Th2 skewing and cytokine imbalance. We examine prototypic FOXP3 mutations in IPEX syndrome alongside related Tregopathies (CTLA4, LRBA, DOCK8, STAT3 GOF, WAS), highlighting shared and distinct cutaneous phenotypes driven by microbiota dysbiosis, barrier disruption, and failed tissue repair. Mechanistic integration reveals self-amplifying inflammatory loops in the skin. Finally, we discuss the evolution of therapies from conventional immunosuppression and hematopoietic stem cell transplantation to precision strategies, including Treg adoptive transfer, CAR-Tregs, FOXP3 gene editing, cytokine biologics, and microbiome modulation. A mechanism-based, tissue-specific approach is essential to restore durable immune tolerance in FOXP3-related cutaneous immunopathology.
Keywords
Subjects

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Available Online from 07 November 2026