Human Memory Helios- FOXP3+ Regulatory T Cells (Tregs) Encompass Induced Tregs That Express Aiolos and Respond to IL-1β by Downregulating Their Suppressor Functions

FOXP3(+) regulatory T cells (Tregs) are critical regulators of self-tolerance and immune homeostasis. In mice and humans, two subsets of FOXP3(+) Tregs have been defined based on their differential expression of Helios, a transcription factor of the Ikaros family. Whereas the origin, specificity, and differential function of the two subsets are as yet a source of controversy, their characterization thus far has been limited by the absence of surface markers to distinguish them. In this article, we show that human memory Helios(+) and Helios(-) Tregs are phenotypically distinct and can be separated ex vivo based on their differential expression of IL-1RI, which is restricted to Helios(-) Tregs, in combination with CCR7. The two populations isolated using this strategy are distinct with respect to the expression of other Ikaros family members. Namely, whereas Eos, which has been reported to mediate FOXP3-dependent gene silencing, is expressed in Helios(+) Tregs, Aiolos, which is involved in the differentiation of T(H)17 and induced Tregs, is instead expressed in Helios(-) Tregs. In addition, whereas both subsets are suppressive ex vivo, Helios(-) Tregs display increased suppressive capacity in comparison to Helios(+) Tregs, but respond to IL-1 beta by downregulating their suppressive activity. Together, these data support the concept that human Helios(-) memory Tregs encompass induced Tregs that can readily respond to changes in the environment by modulating their suppressive capacity.