Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.
Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.
Biol Blood Marrow Transplant. 2019 Oct;25(10):1911-1919. doi: 10.1016/j.bbmt.2019.06.002. Epub 2019 Jun 10.
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.
高剂量化疗和/或放疗在异基因造血细胞移植前严重损害胸腺上皮细胞（TECs），导致移植后免疫恢复不良。IL-22 通过促进再生的作用介导 TEC 的恢复，但发生这种情况的确切机制尚不清楚。在这项研究中，我们发现 IL-22 可改善照射后损伤的胸腺恢复，与 TEC 数量增加有关。这种作用被 JAK1/JAK2 抑制剂鲁索利替尼阻断。IL-22 通过 mTEC1 鼠胸腺上皮细胞系中的 Stat3 依赖性信号通路增加 TEC 数量。这反过来又上调髓样细胞白血病序列 1（Mcl1）的转录，导致 TEC 数量增加。在给予 IL-22 的照射小鼠中也观察到类似的效果。IL-22 缺陷导致照射小鼠的胸腺恢复延迟，并对 Foxn1、Aire 和 Kgf 等与胸腺功能相关的基因水平产生影响。在小鼠中，移植后使用 IL-22 可改善 TEC 的修复，增加胸腺 T 细胞数量，增加 Aire 的胸腺内水平，并增加天然调节性 T 细胞的比例，从而降低慢性移植物抗宿主病（GVHD）的严重程度。我们的数据强调了 IL-22/Stat3/Mcl-1 途径在照射后小鼠 TEC 再生中的关键作用，并强调了用 IL-22 使胸腺 T 细胞功能正常化可降低同种异体移植后 GVHD 的情况。
