Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production

TLDR

FOXP3 is regarded as the most specific marker for natural CD4⁺CD25⁺ T regulatory cells, yet evidence shows that activated human T effector cells also express it, challenging its exclusivity. The study aimed to clarify FOXP3’s role in human Teff cells. The authors examined FOXP3 intensity and kinetics in ex vivo, suppressed, and cell‑line Teff cells. All dividing human Teff cells transiently expressed FOXP3 at lower levels than nTregs, without suppressing FOXP3 target genes or inducing a regulatory phenotype, indicating that FOXP3 expression is a normal activation consequence and cannot serve as an exclusive nTreg marker, thus requiring a reassessment of its role in human immune tolerance.

Abstract

Forkhead box P3 (FOXP3) is currently thought to be the most specific marker for naturally occurring CD4+CD25+ T regulatory cells (nTregs). In mice, expression of FoxP3 is strictly correlated with regulatory activity, whereas increasing evidence suggests that in humans, activated T effector cells (Teffs) may also express FOXP3. In order to better define the role of FOXP3 in human Teff cells, we investigated the intensity and kinetics of expression in ex vivo Teff cells, suppressed Teff cells and Teff cell lines. We found that all dividing Teff cells expressed FOXP3, but only transiently, and at levels that were significantly lower than those in suppressive nTregs. This temporary expression in Teff cells was insufficient to suppress expression of reported targets of FOXP3 repressor activity, including CD127, IL-2 and IFN-γ, and was not correlated with induction of a nTreg phenotype. Thus expression of FOXP3 is a normal consequence of CD4+ T cell activation and, in humans, it can no longer be used as an exclusive marker of nTregs. These data indicate that our current understanding of how FOXP3 contributes to immune tolerance in humans needs to be re-evaluated.