Treg Cell Plasticity as a Driver of Inflammation in Spondyloarthritis and Psoriasis

Ingrid Itzayanna Ortega Mejia^1,2Nayeli Romero-López^1,2Julio César Casasola-Vargas³Ruben Burgos-Vargas³María Lilia Domínguez-López¹José Pablo Romero-López^2*

• ¹Laboratorio de Inmunoquímica 1, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
• ²Laboratorio de patogénesis molecular, edificio A4, Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla de Baz, Estado de México, Mexico
• ³Rheumatology Department, Hospital General de México, Mexico City, Mexico

Regulatory T cells (Tregs) are critical for maintaining immune tolerance by suppressing effector T cell responses. However, in chronic inflammatory diseases such as spondyloarthritis (SpA) and psoriasis (PsO), Tregs can lose their stability and acquire proinflammatory characteristics, a phenomenon known as Treg plasticity. Under inflammatory conditions, Tregs may downregulate FoxP3, upregulate RORγt, and produce cytokines such as IL-17 and IFN-γ, thus losing their suppressive function and contributing to disease progression.In SpA, altered numbers and impaired Treg function have been identified in peripheral blood and synovial fluid. Specific subsets, such as CD161⁺ Tregs with Th17-like features, suggest that inflammatory cytokines and signals like STAT3 activation and ICOS engagement promote pathogenic reprogramming. Genetic factors, including HLA-B27, may further predispose Tregs to instability. Single-cell transcriptomic analyses have provided evidence of shared TCR repertoires between Tregs and effector T cells, reinforcing the concept of lineage plasticity.Similarly, in PsO, skin-resident Tregs exposed to IL-23, IL-6, and IL-21 can acquire a Th17like phenotype, producing IL-17A and exacerbating local inflammation. Environmental factors such as hypoxia also contribute to destabilizing Treg identity. The persistence of pathogenic Tregs, even following therapy blockade of IL-17 or IL-23, highlights the challenge of achieving long-term disease remission.