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 (T_regs) in mice and humans. Evidence from mouse literature suggests that natural FOXP3⁺ T_regs are formed in the thymus and expand in the periphery to contribute significantly to peripheral T_regs. In this review, we discuss recent reports that show that, in humans, the formation of FOXP3⁺ T_regs is a natural consequence of T cell activation and that de novo peripheral generation of FOXP3⁺ T_regs is a much more dominant source of circulating T_regs than natural thymically derived T_regs. We also suggest that the role of T_regs 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 T_regs.