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Biol Blood Marrow Transplant. 2019 Jun 10. pii: S1083-8791(19)30366-0. doi: 10.1016/j.bbmt.2019.06.002. [Epub ahead of print]

IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants.

Author information

1
Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.
2
Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.
3
Department of Pathology, Xuzhou Medical University, Xuzhou, China.
4
Centre for Haematology Research, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom.
5
Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China. Electronic address: lihmd@163.com.

Abstract

High-dose chemotherapy and/or radiation given before an allogeneic hematopoietic cell transplantation severely damage thymic epithelial cells (TECs), resulting in poor post-transplant immune recovery. IL-22 mediates recovery of TECs via a proregenerative 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, post-transplant use of IL-22 improved repair of TECs, increased the numbers of thymus T cells, increased the intrathymic levels of Aire, and increased the 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 the regeneration of TECs after damage from irradiation in mice and highlight circumstances where normalizing thymus T cell function with IL-22 decreases GVHD after allotransplants.

KEYWORDS:

Graft-versus-host disease; IL-22; Thymic epithelial cell; Thymus

PMID:
31195136
DOI:
10.1016/j.bbmt.2019.06.002

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