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

Abstract

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

Figure 1. A model of peripheral T_reg formation in adult humans, as a consequence of activation

Every time there is activation of T cells in the periphery, the responding T cells upregulate FOXP3 and CD25 transiently. This is associated with transient suppressive activity and also some effector functions. The suppressive activity may serve to inhibit untoward responses from lower affinity/potentially cross-reactive T cells. During the response, only a subset of these activated T cells retain FOXP3 and contribute to the peripheral pool of FOXP3⁺ T_regs, persisting for longer periods in the FOXP3⁺ suppressive state. The majority of the activated cells downregulate FOXP3, contract in numbers and contribute to the peripheral memory pool. Such memory cells have the potential to contribute to the peripheral T_reg pool in future activation cycles. Of note, the T cell receptor distribution of the memory pool and the T_reg pool are similar, suggesting common precursors. It is still unclear whether there is direct conversion of “stable” T_regs into memory and/or effector cells in vivo. In the thymus, positive selection of T cells with intermediate affinity for self antigens results in the formation of a population of natural FOXP3⁺ T_regs. While these may be a major source of peripheral T_regs in mice and probably in human infants, most of these may not persist during adult life in humans. Thus, peripherally generated T_regs with diverse antigenic specificities are the major source of circulating T_regs in adult human beings.