Human regulatory T cells: A unique, stable thymic subset or a reversible peripheral state of differentiation?

FOXP3 is probably the best marker available currently for identifying natural regulatory T cells (Tregs) in mice and humans. Evidence from mouse literature suggests that natural FOXP3+ Tregs are formed in the thymus and expand in the periphery to contribute significantly to peripheral Tregs. In this review, we discuss recent reports that show that, in humans, the formation of FOXP3+ Tregs is a natural consequence of T cell activation and that de novo peripheral generation of FOXP3+ Tregs is a much more dominant source of circulating Tregs than natural thymically derived Tregs. We also suggest that the role of Tregs in human diseases must be reviewed in light of these new findings and great caution should be exercised in immunotherapeutic interventions that involve the modulation or generation of putative Tregs.