Regulatory T cells and their role in inflammatory bowel disease: molecular targets, therapeutic strategies and translational advances

Abstract

Regulatory T cells (T_regs) are essential for immune tolerance and for controlling pathological inflammation, particularly in mucosal tissues such as the gastrointestinal tract. Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is increasingly associated with T_reg dysfunction. This dysfunction is marked by loss of lineage stability, impaired suppressive function, and a disrupted balance with pro-inflammatory T helper type 17 (Th17) cells. Advances in molecular immunology have identified key pathways that control T_reg differentiation, epigenetic maintenance, and metabolic signaling. These include interleukin-2/signal transducer and activator of transcription 5 (IL-2/STAT5), forkhead box P3/conserved non-coding DNA sequences 2 (FOXP3/CNS2), mechanistic target of rapamycin (mTOR), and retinoic acid-related orphan receptor gamma t (RORγt) pathways, several of which are genetically linked to IBD susceptibility and offer viable targets for therapeutic development. This structural and biochemical mechanisms contribute to T_reg instability in IBD and evaluates pharmacological strategies aimed at restoring immune balance. Therapeutic strategies include small molecules, antibody therapies, and cell-based approaches that support T_reg expansion, stabilize lineage identity, or enhance suppressive function. We emphasize interventions supported by genetic and translational evidence, positioning T_reg modulation as a promising direction for precision therapy in IBD. The review also discusses ongoing clinical trials and future opportunities involving omics-driven patient stratification, targeted delivery platforms, and chimeric antigen receptor (CAR)-T_reg technologies to improve treatment outcomes.

Keywords: Immunotherapy; Inflammatory bowel disease; Regulatory T cell.