tTregs

Thymus-derived regulatory T cells (tTregs) are a subset of CD4+ regulatory T cells that develop in the thymus and contribute to immune tolerance by limiting self-reactive responses and preventing autoimmunity. They express the transcription factor Foxp3 and the surface marker CD25, among other features.

Origin and markers. tTregs arise when developing thymocytes with intermediate affinity for self-antigens commit to the regulatory lineage, complementing the deletion of strongly self-reactive cells. Foxp3 induction is typically accompanied by epigenetic changes, including demethylation of the FOXP3 TSDR, which is associated with stable lineage commitment. Phenotypic markers include CD4, CD25, and CTLA-4. Helios and neuropilin-1 have been proposed as markers of thymic origin, but their utility remains debated.

Functions and mechanisms. tTregs suppress immune responses through cell-contact–dependent and cytokine-mediated pathways. Key mediators include CTLA-4, consumption of IL-2, and suppressive cytokines such as TGF-β, IL-10, and IL-35. They may also express CD39 and CD73, contributing to adenosine production and local suppression. tTregs act in secondary lymphoid organs and inflamed tissues to limit autoreactive T cell activation and maintain tolerance to self-antigens.

Clinical relevance. tTregs are implicated in autoimmunity when their number or function is impaired. They are also relevant in cancer, where tumor-infiltrating Tregs can dampen anti-tumor immunity. Therapeutic strategies under investigation include low-dose IL-2 to expand Tregs and adoptive transfer of Tregs to promote tolerance in transplantation or autoimmune diseases.

Relation to other Tregs. tTregs are often contrasted with peripherally induced Tregs (pTregs or iTregs) that arise from conventional T cells in the periphery under tolerogenic conditions. tTregs generally display more stable Foxp3 expression due to an epigenetically demethylated TSDR, though this stability can be influenced by inflammatory contexts.