Comment on “Differentiation of IL-17–Producing Effector and Regulatory Human T Cells from Lineage-Committed Naive Precursors”

In their study, Mercer et al. (1) show that IL-17–producing T cells differentiate from CCR6⁺ naive CD4 T cells from adult peripheral blood, both conventional and T regulatory cells (nTregs). These results are in line with our recent data showing that T_H17 cells can differentiate from nTregs in adult circulating lymphocytes (2). The authors also obtained differentiation of T_H17 cells from total CD4⁺CCR6⁺ T cells from umbilical cord blood (UBC), although significantly less efficiently. Because of the low proportions of CCR6⁺ cells in UBC, however, they could not assess CCR6⁺ conventional CD4 T cells and Tregs separately. As mentioned by the authors, IL-17–secreting cells are found among Helios^– Tregs that likely correspond to peripherally-induced Tregs rather than thymically-derived Tregs. As was recently reported, nTregs in adults include Helios⁺ and Helios⁻ cells, the latter representing ∼30% of total nTregs (3). We showed, however, that Helios⁻ Tregs are undetectable in UBC, in which nTregs are, in contrast, abundant (4). To directly assess the presence of T_H17 precursors in nTregs from UBC, we isolated them by cell sorting and differentiated them in the presence of T_H17 polarizing factors. However, we failed to obtain a significant differentiation of IL-17–secreting cells from UBC nTregs. Thus, whereas differentiation of T_H17 cells can indeed occur from phenotypically naive Tregs of adults, most FOXP3⁺Helios^– Treg precursors of T_H17 cells appear to develop in the periphery after birth, and may therefore be, despite their naive phenotype, peripherally-induced Tregs rather than thymically-derived Tregs.