IL-38通过PD-1/PD-L1通路调控脓毒症状态下调节性T细胞免疫效应及机制

IL-38是最新近发现的抑炎因子，在炎症和免疫性疾病中具有重要的免疫效应，但在脓毒症免疫功能障碍中的作用尚未报道。我们预实验发现，IL-38及其受体在调节性T细胞（Tregs）中表达，且在内毒素刺激后表达显著上调。同时，应用重组IL-38能显著增强脓毒症小鼠Tregs的免疫活性，提示IL-38在脓毒症Tregs免疫功能紊乱中具有重要的意义。本项目拟研究脓毒症状态下IL-38的表达规律及其对Tregs免疫功能的影响，来明确IL-38与Tregs功能紊乱的内在联系，并进一步阐明IL-38通过PD-1/PD-L1-AKT/mTORC1信号途径影响Tregs免疫活性。实验采用IL-38、PD-L1基因敲除小鼠模型，通过对该信号通路中的关键分子PD-L1和mTORC1表达进行干预，从不同层面探讨IL-38介导脓毒症时Tregs免疫效应及其关键信号通路，为脓毒症免疫调理治疗提供新思路。

As a newly-discovered anti-inflammatory cytokine, IL-38 plays a key role in the pathogenesis of various inflammatory and autoimmune diseases. Until now, significance of IL-38 in sepsis-induced dysfunction remains unclear. We recently found that IL-38 and its receptor were expressed in murine regulatory T cells (Tregs) and their expression were markedly up-regulated after LPS stimulation. Besides, recombinant IL-38 could obviously improve the activity of Tregs. With both cell and animal experiments and clinical observation, the present project will be conducted to investigate the effect of IL-38 on Treg activity during sepsis. Using cell or animal model of IL-38-knockdown or PD-L1-knockdown, we will explore the contribution of IL-38-mediated signaling (PD-1/PD-L1-AKT/mTORC1 pathway) in Tregs during sepsis. Taken together, our study will help to shed a fresh light on the immunological effect of IL-38 and its regulatory mechanisms, which develops a novel immunomodulatory strategy for the treatment of sepsis.