gms | German Medical Science

Regulatory T cells (Tregs) are recognized as a subset of CD4+ T cells characterized by expression of the hallmark transcription factor Foxp3 and their central function in immune tolerance [1]. Further, Tregs play a role in bone homeostasis, enhancing bone formation [2]. Under inflammatory conditions, Tregs may acquire an effector cell phenotype which may contribute to autoimmunity. In the context of systemic juvenile idiopathic arthritis, IL-1 is postulated to be a potent modulator of adaptive immunity promoting Tregs to transdifferentiate into proinflammatory T helper 17 cells (Th17) [3]. Recently, we identified a population of IL-1β-driven osteoclastogenic Tregs, which are characterized by high expression of RANKL. These RANKLhi Tregs induced differentiation of osteoclasts, which contributed to bone erosion in IL-1 receptor antagonist (IL-1Ra) deficient mice, while maintaining suppressive function [4]. The effect of IL-1β on human Tregs however remains to be clarified, which was addressed in this study. Naïve CD4+ T cells were isolated from peripheral blood of healthy donors and underwent in vitro Treg differentiation using the CellXVivo differentiation kit in the presence of IL-1β. Following five days of differentiation, the Treg phenotype was investigated through FACS analysis. The suppressive function and osteoclastogenic capacity were studied in co-cultures with T effector cells and osteoclasts. Our data demonstrate that Tregs expressed the IL-1 receptor (IL-1R) during differentiation with a peak on day two, but not at mature stage. IL-1β-derived Tregs showed increased expression of TGF-β and IL-17, while maintaining stable Foxp3 expression and suppressive function. Tregs differentiated in the presence of IL-1β further exhibited an increased population of Foxp3loRANKLhi cells as well as elevated levels of RANKL surface expression. Our data also indicate an osteoclastogenic effect of IL-1β-driven Tregs, which however needs to be further investigated on more donors. Together, these findings identify a population of IL-1β-derived Tregs, characterized by lineage stability and increased RANKL expression with a potential osteoclastogenic effect.