Tregs

Regulatory T cells (Tregs) are a specialized subset of CD4+ T lymphocytes that maintain immune tolerance and prevent excessive or inappropriate immune activation. In humans, Tregs are typically identified as CD4+ T cells that express high levels of CD25 (IL-2 receptor α chain) and the transcription factor FOXP3; additional markers such as CTLA-4 and low/negative CD127 are often used. Tregs include thymus-derived (tTregs) and peripherally induced (iTregs) populations. tTregs develop in the thymus upon recognition of self-antigens with intermediate affinity; iTregs arise in peripheral tissues in tolerogenic environments, often in response to non-self antigens in the presence of TGF-β and IL-2.

Functionally, Tregs suppress other T cells and regulate innate immune cells to limit immune responses. Mechanisms include cell contact-dependent suppression via CTLA-4, production of immunosuppressive cytokines such as IL-10, TGF-β, and IL-35, metabolic disruption through consumption of IL-2 and generation of adenosine via CD39/CD73, and cytolytic activity in some contexts. FOXP3 acts as a master regulator of the Treg gene program, and a stable Treg lineage is associated with a demethylated TSDR in the FOXP3 locus; marker-based identification can be imperfect, with Helios and other markers contributing to debate on tTreg vs iTreg origin.

Clinical relevance: Tregs are central to preventing autoimmunity; FOXP3 mutations cause the IPEX syndrome in humans, and mutations or epigenetic defects affecting FOXP3/TSDR can lead to dysregulated tolerance in model systems. In cancer, Tregs can suppress anti-tumor immunity and often correlate with poor prognosis; in transplantation or allergy they promote tolerance. Therapeutically, adoptive transfer or expansion of Tregs is being explored for graft-versus-host disease and autoimmune diseases, but challenges include ensuring stability, preventing lineage conversion, and scalable manufacturing.