The alarmin IL33 orchestrates type 2 immune-mediated control of thymus regeneration

As the primary site of T-cell development, the thymus dictates immune competency of the host. The rates of thymus function are not constant, and thymus regeneration is essential to restore new T-cell production following tissue damage from environmental factors and therapeutic interventions. Here, we show the alarmin interleukin (IL) 33 is a product of Sca1 + thymic mesenchyme both necessary and sufficient for thymus regeneration via a type 2 innate immune network. IL33 stimulates expansion of IL5-producing type 2 innate lymphoid cells (ILC2), which triggers a cellular switch in the intrathymic availability of IL4. This enables eosinophil production of IL4 to re-establish thymic mesenchyme prior to recovery of thymopoiesis-inducing epithelial compartments. Collectively, we identify a positive feedback mechanism of type 2 innate immunity that regulates the recovery of thymus function following tissue injury. Although thymic function declines with age, the thymus also has the ability to regenerate following injury. Here, the authors demonstrate that IL-33 and type-2 innate lymphoid cells trigger the expansion of eosinophils following radiation injury, which in turn produce IL-4 to stimulate the recovery of the thymus mesenchyme during thymus regeneration.