Group 2 innate lymphoid cells (ILC2s) are a specialized subset of lymphoid effector cells that are critically involved in allergic responses; however, the mechanisms of their regulation remain unclear. We report that conditional deletion of the E3 ubiquitin ligase VHL in innate lymphoid progenitors minimally affected early-stage bone marrow ILC2s but caused a selective and intrinsic decrease in mature ILC2 numbers in peripheral non-lymphoid tissues, resulting in reduced type 2 immune responses. VHL deficiency caused the accumulation of hypoxia-inducible factor 1α (HIF1α) and attenuated interleukin-33 (IL-33) receptor ST2 expression, which was rectified by HIF1α ablation or inhibition. HIF1α-driven expression of the glycolytic enzyme pyruvate kinase M2 downmodulated ST2 expression via epigenetic modification and inhibited IL-33-induced ILC2 development. Our study indicates that the VHL-HIF-glycolysis axis is essential for the late-stage maturation and function of ILC2s via targeting IL-33-ST2 pathway.

第2组先天性淋巴样细胞（ILC2s）是淋巴样效应细胞的一个特殊子集，其主要参与变态反应。但是，它们的调节机制仍不清楚。我们报告说，先天性淋巴祖细胞中的E3泛素连接酶VHL的条件性删除对早期骨髓ILC2的影响最小，但在外周非淋巴组织中导致成熟ILC2数量的选择性和内在降低，从而导致2型免疫反应降低。VHL缺乏导致缺氧诱导因子1α（HIF1α）的积累和白介素33（IL-33）受体ST2的表达减弱，这可以通过HIF1α的消融或抑制来纠正。HIF1α驱动的糖酵解丙酮酸激酶M2的表达通过表观遗传修饰下调了ST2的表达，并抑制了IL-33诱导的ILC2的发育。我们的研究表明，通过靶向IL-33-ST2途径，VHL-HIF糖酵解轴对于ILC2的后期成熟和功能至关重要。