Regulatory T Cell (Treg)

Regulatory T cells are the suppressive arm of the CD4 compartment, identified by high CD25, low CD127 and expression of FOXP3. Some are selected in the thymus against self-antigen, others induced in the periphery, particularly in the gut. They suppress by several non-redundant routes: consuming interleukin-2 through their high-affinity receptor and starving effector cells, stripping CD80 and CD86 from antigen-presenting cells through CTLA-4, releasing IL-10 and TGF-beta, and generating adenosine.

Their necessity is demonstrated by a single gene. Loss-of-function mutation in FOXP3 causes IPEX syndrome, a fatal early autoimmune disease of endocrine organs, gut and skin. In the other direction, blocking CTLA-4 with ipilimumab releases suppression and produces a characteristic set of immune-related adverse events, and tumours are frequently infiltrated by regulatory T cells that blunt antitumour responses.

That bidirectionality is the point: more regulatory T cells is desirable in autoimmunity and transplantation and undesirable in cancer, so a compound described as raising them has not thereby been shown beneficial. Low-dose interleukin-2, which expands them preferentially because of that receptor affinity, has been trialled on this logic in autoimmune disease, while high-dose interleukin-2 was used to drive antitumour responses.

The technical trap is FOXP3 itself. In humans, unlike mice, activated conventional CD4 T cells transiently express it without gaining suppressive function, so FOXP3 staining alone overcounts regulatory T cells in an activated sample. Frequency is in any case a poor surrogate for suppression, which has to be shown in a functional assay; a report that a peptide raises regulatory T cell percentage with no such assay and no clinical endpoint has measured a phenotype marker.