Interleukin-22 accelerates thymus regeneration via Stat3/Mcl-1 and decreases chronic graft-versus-host disease in mice after allotransplants

Abstract High-dose chemotherapy and/or radiation given before an allogeneic hematopoietic cell transplantation severely damage thymic epithelial cells (TECs) resulting in poor posttransplant immune recovery. IL-22 mediates recovery of TECs via a pro-regenerative effect but the precise mechanism by which this occurs is unknown. In this study, we found IL-22 improved thymus recovery after damage from irradiation in association with increased number of TECs. This effect was blocked by ruxolitinib, a JAK1 / JAK2 -inhibitor. IL-22 increased the number of TECs via a Stat3-dependent signaling in the mTEC1 murine thymic epithelial cell line. This, in turn, upregulated transcription of myeloid cell leukemia sequence 1 ( Mcl1 ) resulting in increased number of TECs. Similar effects were seen in irradiated mice given IL-22. Defects in IL-22 resulted in delayed thymus recovery in irradiated mice and had an impact on levels of thymus function related genes such as Foxn1, Aire and Kgf . In mice, posttransplant use of IL-22 improved repair of TECs, increased the numbers of thymus T cells, increased the intra-thymic levels of Aire and increased proportion of natural regulatory T cells resulting in decreased severity of chronic graft-versus-host disease (GVHD). Our data highlight the critical role of the IL-22/Stat3/Mcl-1 pathway in regeneration of TECs after damage from irradiation in mice and highlight circumstances where normalizing thymus T-cell function with IL-22 decreases GVHD post allotransplants.