pTregs

Peripheral regulatory T cells, or pTregs, are a subset of CD4+ regulatory T cells that acquire the transcription factor FOXP3 and regulatory function outside the thymus, in contrast to thymus-derived tTregs (also called nTregs). pTregs originate from conventional CD4+ T cells upon antigen encounter in peripheral tissues, with the gut-associated lymphoid tissue being a prominent site where signals such as transforming growth factor-beta (TGF-β), interleukin-2 (IL-2), and retinoic acid promote FOXP3 induction.

Development and markers: In addition to FOXP3, pTregs commonly express CD25 and CTLA-4. Markers historically used to distinguish thymic-derived cells, such as Helios and Neuropilin-1, are not universally reliable and remain debated. The stability of FOXP3 expression in pTregs is linked to epigenetic features of the Foxp3 locus, particularly the Treg-specific demethylated region (TSDR); pTregs often show more variable epigenetic stabilization than thymic-derived Tregs.

Function and mechanisms: pTregs suppress effector T cell responses through multiple pathways, including production of anti-inflammatory cytokines like IL-10 and TGF-β, CTLA-4–mediated modulation of antigen-presenting cells, and metabolic disruption of target cells. They play a key role in maintaining tolerance to dietary antigens and to commensal microbiota, especially at mucosal surfaces, contributing to immune homeostasis.

Biological and clinical relevance: Disruption of pTreg generation or stability can contribute to inflammatory diseases such as inflammatory bowel disease, whereas in cancer, their suppressive activity can hinder anti-tumor immunity. Therapeutic approaches seek to promote pTreg induction for tolerance in autoimmunity or transplantation, or to limit pTreg activity when immune suppression interferes with cancer immunotherapy.