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

摘要

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.