Umbilical cord blood-derived Helios-positive regulatory T cells promote angiogenesis in acute lymphoblastic leukemia in mice via CCL22 and the VEGFA-VEGFR2 pathway

Regulatory T cells (Tregs) maintain immune homeostasis and modulate tumor-induced neovascularization. However, the mechanisms underlying the role of Tregs in acute lymphoblastic leukemia (ALL) remain to be elucidated. Helios, combined with forkhead box P3, is considered a suitable marker for discriminating functional Tregs. In the present study, a microenvironment was created with a high proportion of Helios(+) Tregs in T cell-deficient nude mice to determine the mechanism underlying Tregs expressing Helios in ALL. It was revealed that umbilical cord blood-derived Helios(+) Tregs had proliferation and immunosuppression abilities similar to those of normal pediatric Tregs. The accumulation of Helios(+) Tregs accelerated leukemogenesis and the infiltration of leukemic cells into the bone marrow. Importantly, a high expression of Helios in Tregs promoted angiogenesis in the bone marrow via the vascular endothelial growth factor (VEGF)A/VEGF receptor 2 (VEGFR2) pathway. Furthermore, the expression of chemokine CC-chemokine ligand 22 (CCL22) in the bone marrow and serum of ALL mice infused with Helios(high) Treg cells was increased. The results demonstrated that Helios promotes the secretion of chemokine CCL22, which may recruit more Tregs into the bone marrow. Increased Helios(+) Treg cells promoted angiogenesis in the bone marrow of ALL mice via the VEGFA/VEGFR2 pathway. Therefore, Helios may be a target to manipulate Treg activity in clinical settings.