When discovered in the early 2000s, interleukin-33 (IL-33) was characterized as a potent driver of type 2 immunity and implicated in parasite clearance, as well as asthma, allergy, and lung fibrosis. Yet research in other models has since revealed that IL-33 is a highly pleiotropic molecule with diverse functions. These activities are supported by elusive release mechanisms and diverse expression of the IL-33 receptor, STimulation 2 (ST2), on both immune and stromal cells. Interestingly, IL-33 also supports type 1 immune responses during viral and tumor immunity and after allogeneic hematopoietic stem cell transplantation. Yet the IL-33–ST2 axis is also critical to the establishment of systemic homeostasis and tissue repair and regeneration. Despite these recent findings, the mechanisms by which IL-33 governs the balance between immunity and homeostasis or can support both effective repair and pathogenic fibrosis are poorly understood. As such, ongoing research is trying to understand the potential reparative and regulatory versus pro-inflammatory and pro-fibrotic roles for IL-33 in transplantation. This review provides an overview of the emerging regenerative role of IL-33 in organ homeostasis and tissue repair as it relates to transplantation immunology. It also outlines the known impacts of IL-33 in commonly transplanted solid organs and covers the envisioned roles for IL-33 in ischemia-reperfusion injury, rejection, and tolerance. Finally, we give a comprehensive summary of its effects on different cell populations involved in these processes, including ST2+ regulatory T cells, innate lymphoid cell type 2, as well as significant myeloid cell populations.

Suppressive and reparative regulatory T cell (Treg) functions are described. However, in transplantation (Tx), recipient immune responses to persistent MHC differences will sustain injury and impact repair. The development of immunosuppressant-resistant graft vasculopathy and fibrosis, or chronic rejection (CR) remains a leading cause of death post-heart Tx (HTx) and may reflect failed tissue repair. We tested the hypothesis that Treg repair responses become dysregulated due to sustained alloreactive immune responses. Our studies utilized IL-33 as a model injury signal, or damage-associated molecular pattern (DAMP) and B6 (H-2b) CD45.1+ mice received heterotopic HTx from MHCII-mismatched Bm12 (H2-I-Abm12) donors that were IL-33-deficient or competent. On day (d)14, scRNAseq and CITE-seq were used to compare CD45.1+ cells from HTx digests (n=4). IL-33 modulated >800 genes in HTx-infiltrating Treg, including the growth factor amphiregulin (Areg; 2.25x; P=0.0241). Areg is implicated in tissue repair, yet when B6 Foxp3YFP-CrexAregfl/fl and Foxp3YFP-Cre mice receiving Bm12 HTx were assessed at d100 (n=6–10), the deletion of Areg in Treg protected against CR. Using IncuCyte Live-Cell imaging, it was clear that Areg from Treg stimulated fibroblast proliferation and migration. Tregs stimulated with IL-2 alone or with IL-33 were assessed at d14 or d21 for CpG methylation of Treg-associated genes. These data revealed that sustained exposure to IL-33 increased methylation of Foxp3, suggesting that sustained DAMP stimulation makes Treg unstable. In total, our studies identify how a sustained and dysregulated repair response involving interactions between fibroblasts and recipient Treg contributes to the progression of HTx CR. Supported by grants from NIH (F30AI147437, T32 CA082084) (GKD), NIH (R01HL122489, R01AR073527) (HRT)

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