Ym1 induces RELM alpha and rescues IL-4R alpha deficiency in lung repair during nematode infection

Ym1 and RELM alpha are established effector molecules closely synonymous with Th2-type inflammation and associated pathology. Here, we show that whilst largely dependent on IL-4R alpha signaling during a type 2 response, Ym1 and RELM alpha also have IL-4R alpha-independent expression patterns in the lung. Notably, we found that Ym1 has opposing effects on type 2 immunity during nematode infection depending on whether it is expressed at the time of innate or adaptive responses. During the lung migratory stage of Nippostrongylus brasiliensis, Ym1 promoted the subsequent reparative type 2 response but once that response was established, IL-4R alpha-dependent Ym1 was important for limiting the magnitude of type 2 cytokine production from both CD4+ T cells and innate lymphoid cells in the lung. Importantly, our study demonstrates that delivery of Ym1to IL-4R alpha deficient animals drives RELM alpha production and overcomes lung repair deficits in mice deficient in type 2 immunity. Together, Ym1 and RELM alpha, exhibit time and dose-dependent interactions that determines the outcome of lung repair during nematode infection.