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

Abstract

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 TH17 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-1β 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.

Cyclosporine restores hematopoietic function by compensating for decreased Tregs in patients with pure red cell aplasia and acquired aplastic anemia

“…1b). This finding was consistent with previous reports [14][15][16][17]. Both subsets highly expressed CTLA4, CCR4 and contained approximately 12 % Ki67 + cells, indicating that the two T cell subsets were activated in vivo (Fig.…”

IL-1R1 is expressed on both Helios+ and Helios−FoxP3+CD4+ T cells in the rheumatic joint

“…Helios, a transcription factor belonging to the Ikaros family, has been studied extensively in the context of human T reg in health and disease [14,[16][17][18][19][20]36]. We have a longstanding interest in the rheumatic joint, a site of inflammation characterized by extensive cell influx and proliferation and where, in addition to activated memory effector T cells, T regs are also enriched significantly compared to PB [23].…”

“…Of note, a recent study demonstrated that the chemokine receptor CCR7 in combination with the cytokine receptor IL-1R1 was restricted largely to the Helios-negative subpopulation of FoxP3 1 T cells [20]. Hence, we analysed if these markers could also be applied to Helios Fig.…”

“…However, it has been of interest to distinguish Helios 1 from Helios 2 T regs as some functional differences have been suggested, such as the ability to produce cytokines [18,19]. Recently, surface expression of IL-1R1 (IL-1 receptor type 1) in conjunction with CCR7 has been shown to be a useful combination of cell surface markers to distinguish Helios 2 T regs from Helios 1 T cells [20]. The IL-1R1 is expressed predominantly on T cells, fibroblasts and endothelial cells, where it conducts its biological inflammatory functions by binding IL-1a and IL-1b [21].…”

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

“…28 Conversely, IL-17 and Helios expression tended to be mutually exclusive (Fig. 5F, left), according to the intrinsic stability of Helios high Tregs 1,16,29 and to the segregation between Helios and RORgt expression in gut Tregs. 30 OX40 expression was similarly distributed in IL-17-positive and -negative cells (Fig.…”