Regulatory T cells exhibit differential therapeutic effects across tissues during chronic autoimmune inflammation.

Current therapies for autoimmune diseases rely largely on non-specific immunosuppression, which can lead to adverse effects such as malignancy and severe infections. Treg-based therapies have therefore attracted attention as a more targeted approach, particularly in preventive or early-stage settings. However, their efficacy after disease onset, especially in chronic inflammation, remains poorly established. Furthermore, it remains unclear whether Treg therapy exerts uniform therapeutic effects across tissues within the same individual. Here, we demonstrate that Tregs retain therapeutic potential in chronic autoimmune inflammation, but their efficacy differs between tissues. Using a TCR-retrogenic mouse model, in which monoclonal autoreactive CD4+ T cells drive spontaneous chronic dermatitis and arthritis, polyclonal Treg administration effectively resolved chronic dermatitis but only limited disease progression in chronic arthritis. Despite these differences in outcomes, transferred Tregs were detected in local tissues and draining lymph nodes, suggesting that tissue-specific environments may underlie differential therapeutic responsiveness. To investigate the basis of this difference, we performed microarray and GSVA-based pathway analyses. Under untreated conditions, skin and joint tissues exhibited distinct baseline pathway activity patterns, with the skin showing higher activity of the Hippo signaling pathway, a growth-regulatory pathway, and the joints displaying stronger enrichment of inflammation-related pathways, including complement- and angiogenesis-associated pathways. Following Treg administration, skin-but not joint-tissue showed pathway modulation, including increased Wnt and decreased IL-17 signaling pathway activity, consistent with a more reparative environment. These findings indicate that distinct inflammatory environments underlie differential responsiveness to Treg therapy across tissues, highlighting their context-dependent therapeutic potential in chronic autoimmune inflammation.