Beyond Suppression: The Plasticity, Dysfunction, and Therapeutic Reprogramming of Regulatory T Cells in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of the gut, whose pathogenesis is closely related to immune dysregulation. Regulatory T cells (Tregs), as a key cell population maintaining intestinal immune tolerance, exhibit not only reduced frequency but, more critically, profound functional deficiencies, including the generation of pro-inflammatory ex-Tregs, and loss of lineage stability in the inflamed gut microenvironment of IBD. This review systematically delineates the sophisticated biological characteristics of Tregs, with a particular focus on the epigenetic and metabolic checkpoints that govern their stability. We critically summarize the aberrant changes of Tregs in IBD, emphasizing mechanisms such as inflammatory cytokine-induced Treg plasticity (e.g., Th1-like or Th17-like conversion) and microbiota-metabolite axis-mediated functional modulation. Furthermore, we provide an in-depth analysis of emerging therapeutic strategies aimed at restoring Treg suppressive capacity, including selective cytokine therapy (e.g., low-dose/engineered IL-2), adoptive transfer of engineered antigen-specific Tregs (including CAR-Tregs), microbiome/dietary interventions, and pharmacological modulation of Treg differentiation. We also discuss the disrupted crosstalk between Tregs and other innate and adaptive immune cells within the IBD milieu. Finally, this review highlights how cutting-edge technologies like single-cell multi-omics and spatial transcriptomics are delineating the heterogeneous landscape and uncovering novel, disease-specific Treg subpopulations, thereby paving the way for precise Treg-targeting therapies. Unlike previous reviews that broadly catalog Treg abnormalities, this review offers a refined conceptual framework centered on the critical distinction between lineage-defective ex-Tregs and exhausted effector Tregs (eTregs), and integrates recent multi-omics insights to redefine Treg functional failure in IBD.