Regulatory T cell

Regulatory T cells (Tregs) are the CD4+ T lymphocyte subset that enforces peripheral tolerance. They are defined by the transcription factor FOXP3, with HELIOS expressed in many but not all cells, and identified in practice by high CD25 and low CD127 surface expression; stable identity depends less on FOXP3 alone than on demethylation of a conserved regulatory element that keeps its expression fixed. Tregs arise in two ways — as thymic Tregs selected on self antigen, and as peripherally induced Tregs converted from naive CD4+ cells at mucosal surfaces, where dietary and microbial antigens require tolerance. What their necessity looks like is clearest in its absence: loss-of-function mutation of FOXP3 causes IPEX syndrome, a fatal multi-organ autoimmunity of infancy, and the equivalent mutation is lethal in mice.

Suppression works through several non-redundant mechanisms rather than one. Tregs secrete cytokine mediators including interleukin-10, transforming growth factor beta and interleukin-35; they consume interleukin-2 through high-affinity CD25, starving neighboring effector cells of a growth factor they cannot make in sufficient quantity; they strip CD80 and CD86 from antigen-presenting cells by CTLA-4-mediated transendocytosis, removing the costimulation naive T cells require; and they generate adenosine through the ectoenzymes CD39 and CD73. After antigen-specific activation they can express activation markers such as CD134 (OX40) and CD137 (4-1BB), but these markers do not by themselves identify Tregs or establish antigen specificity in tissue.

The same machinery is beneficial or harmful depending on setting, so therapy runs in both directions. Boosting Tregs — by low-dose interleukin-2, adoptive transfer, or antigen-specific engineered cells — is pursued in autoimmunity, transplantation and graft-versus-host disease, where impaired Treg recovery in the chronic form has prompted strategies to restore peripheral numbers. Depleting or destabilizing them is pursued in oncology, since Tregs accumulate in tumors, are recruited and reinforced by tumor-derived signals including exosomes and TNFR2 engagement, and are a principal reason tumors evade immune attack; the difficulty is that agents which reach intratumoral Tregs tend to reach the systemic pool as well, trading tumor control for autoimmunity. Treg function also declines with age, contributing to dysregulated systemic immunity.