Regulatory T cell dysfunction and therapeutic advances in rheumatoid arthritis, psoriasis, vitiligo, and systemic lupus erythematosus.

Abstract

Regulatory T cells (Tregs) are a critical immunosuppressive subset of CD4+ T cells, whose lineage stability and suppressive function rely on the transcription factor FOXP3. Within inflamed tissue microenvironments, Tregs maintain immune homeostasis and preserve tissue integrity via multiple mechanisms, including secretion of anti-inflammatory cytokines such as IL-10 and TGF-β, CD39/CD73-mediated adenosine metabolic pathways, and CTLA-4-dependent cell-contact inhibition. Nevertheless, in autoimmune diseases including systemic lupus erythematosus, psoriasis, rheumatoid arthritis, and vitiligo, Tregs frequently exhibit reduced frequency, impaired suppressive capacity, and conversion to pro-inflammatory phenotypes, accompanied by excessive activation of Th17 cells. This results in severe disruption of the Th17/Treg immune axis, which drives chronic inflammation and tissue damage. In terms of therapeutic strategies, low-dose IL-2 selectively expands functional Tregs to restore systemic immune balance. Rapamycin reverses Treg depletion and dysfunction by inhibiting the mTOR pathway, thereby reconstructing an immune-tolerant tissue microenvironment. Furthermore, engineered CAR-Treg cells exert antigen-specific anti-inflammatory effects, offering a novel therapeutic option for autoimmune diseases. Although these interventions have demonstrated promising efficacy in preclinical and early clinical studies, their clinical translation is hindered by major bottlenecks, such as precise targeting of inflamed tissues, sustained stability of Treg function under inflammatory conditions, and avoidance of systemic immunosuppressive risks. This paper systematically reviews the regulatory mechanisms and targeted therapeutic advances of Tregs in autoimmune diseases linked to Th17/Treg imbalance, analyzes the limitations of current research, and provides theoretical evidence for precision immunotherapy of autoimmune diseases.