STAT3/Mcl-1通路调控异基因造血干细胞移植后胸腺修复的作用和机制研究

异基因造血干细胞移植（allo-HSCT）后良好的T细胞免疫重建应包括T细胞免疫防御功能的恢复和稳定的免疫耐受形成。受者T细胞免疫重建迟缓会反复感染，而免疫耐受形成异常可导致移植物抗宿主病。调节外周T细胞增殖和活化难以从根本上解决上述难题。胸腺是T细胞发育成熟的场所，胸腺上皮细胞（TECs）在allo-HSCT中功能严重受损，TECs数量和功能的恢复是实现良好T细胞免疫重建的基础。我们前期证实IL-22是调控TECs增殖的关键因素，IL-22可能通过STAT3/Mcl-1通路调控TECs增殖。在此基础上，本项目拟研究IL-22/STAT3调控Mcl-1的机制及其对allo-HSCT后TECs修复的影响，进一步明确IL-22/STAT3/Mcl-1通路在T细胞免疫重建和免疫耐受中的作用。因此，探索促进TECs修复的策略将为改善allo-HSCT后T细胞免疫重建和免疫耐受形成提供新的思路。

Favorable reconstitution of T-cell immunity post allogeneic hematopoietic stem cell transplantation (allo-HSCT) consists of recovered function of immune defense and immune tolerance. Low level of T-cell is a major reason for posttransplant infection. Dysfunction of immune tolerance often results in graft-versus-host disease (GVHD). Stimulating proliferation of peripheral mature T cells accelerates recovery of T-cell count, but increases the risk of development of severe GVHD. Thymus is the primary organ for maturation of T cells. Developing thymocytes migrate and obtain vital signals from a basic structure weaved by thymic epithelial cells (TECs), which are inevitably injured by stresses during allo-HSCT. Recovery of TECs paves a way for favorable reconstitution of T-cell immunity, with both rapidly recovered cell number and refined self-tolerance. We previously proved that IL-22 is critical in mediating proliferation of TECs after injury. IL-22/STAT3 stimulates proliferation of TECs in a Mcl-1 dependent manner. Based on our previous findings, we interrogate how IL-22 signaling regulates activation of STAT3/Mcl-1 pathway in thymus. In this study, we plan to explore the role of IL-22/STAT3/Mcl-1 pathway in regulating recovery of TECs and thymus after allo-HSCT, and to uncover the impact of exogenous IL-22 on reconstitution of T-cell immunity. Regulation on recovery of TECs might represent a new strategy in improving reconstitution of T-cell immunity after allo-HSCT.