*Purpose: IL-33 is considered an alarmin secreted in response to tissue damage. While it is elaborated by the lung allograft as part of ischemia-reperfusion injury its role in lung graft homeostasis is unknown. Meanwhile, it serves as regulating cytokine in both type1 and type2 immune response. Given the importance of IL-33 in local immunity, we sought to define its role in lung transplantation.

*Methods: Left single lung transplants were performed as previously described with co-stimulatory blockade (CSB) immunosuppression and evaluated at day 7. A hilar clamping model of ischemia-reperfusion injury (IRI) was used to confirm some results.

*Results: IL-33 deficient lung allografts on a C57BL/6 background transplanted into Balb/c mice were rejected despite CSB immunosuppression. This was characterized by an increase in the ISHLT rejection grades, fewer tolerogenic eosinophils and more T cells, and lower production of IL-5 (Figure 1). Thus IL-33 plays a role in lung allograft acceptance. Using the hilar clamp model of IRI we were able to prove that IL-33 levels depended on ischemic injury and that IL-5 secretion by ILC2 depended on IL-33 (Figure 2). ILC2 deficient lung allografts demonstrated low IL-5 production after transplantation and a similar rejection pattern observed on IL-33 deficient lung allografts (Figure 3).

*Conclusions: Our data expands on our previous observations that eosinophil homeostasis and migration to the lung graft, which depends on IL-5, is critical to tolerance induction. We now demonstrate that IL-33 induced by IRI activates donor-derived ILC2s which secrete IL-5 into the local environment to facilitate eosinophil-mediated tolerance. Taken together, donor-derived IL-33 initiates a protective mechanism against allograft rejection.

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