nTreg

nTregs, or natural regulatory T cells, are a subset of CD4+ T cells that develop in the thymus. They are essential for maintaining self-tolerance by suppressing autoreactive T cells and preventing autoimmune responses.

They express the transcription factor FOXP3 and typically high levels of CD25 (IL-2 receptor alpha). Their development and maintenance depend on IL-2 signaling. A distinguishing feature is the demethylation of the Treg-specific demethylated region (TSDR) in the FOXP3 locus, which supports a stable regulatory lineage. Induced regulatory T cells (iTregs) that arise outside the thymus can share FOXP3 expression but often show different TSDR methylation status.

nTregs suppress immune responses through multiple mechanisms. They express CTLA-4, can produce immunosuppressive cytokines such as IL-10, TGF-β, and IL-35, and can mediate suppression via cell-contact–dependent pathways. They also disrupt effector T cell metabolism by consuming IL-2 and can generate immunosuppressive adenosine through the CD39/CD73 axis. In some contexts, they may kill target cells via granzyme B and perforin. Their function is context-dependent and cooperative with other regulatory populations.

In disease, nTregs are critical for preventing autoimmunity; loss or mutation of FOXP3 causes fatal autoimmune syndromes in mice and humans. However, they can hinder anti-tumor immunity and contribute to persistent infections or graft tolerance in transplantation. Markers such as Helios and Neuropilin-1 have been proposed to indicate thymic origin but remain controversial; TSDR methylation status is a more robust indicator. Differences between species and age-related thymic involution affect nTreg development and maintenance.