Treg细胞通过IL-10/JAK1/STAT3通路抑制巨噬细胞对马尔尼菲篮状菌清除作用的研究

马尔尼菲篮状菌（TM）感染后巨噬细胞对TM孢子的吞噬增多但清除能力下降是导致TM播散及慢性持续感染的机制之一。我们前期研究发现：TM可诱导Treg细胞的分化；TM还可以促进Treg细胞分泌IL-10增多；TM感染小鼠的肺巨噬细胞STAT3磷酸化增加。文献报道STAT3抑制巨噬细胞内iNOS表达和NO合成，并抑制IL-6, TNF-α, IFN-γ分泌。我们假设Treg细胞在TM逃逸机体免疫机制中有重要作用。本项目将在前期研究基础上，采用在Treg细胞上条件性敲除IL-10的小鼠模型和TM-巨噬细胞-Treg体外共培养实验验证以下假设：Treg细胞通过IL-10/JAK1/STAT3介导的信号通路增强巨噬细胞吞噬TM功能但抑制巨噬细胞iNOS-NO产生，从而降低胞内TM的清除功能。项目的完成将进一步阐明TM感染的宿主免疫调控机制，为TM感染中有针对性的治疗免疫干预奠定基础。

Macrophage phagocytosis of Talaromyces marneffei (TM) spores increased but their clearance ability decreased in TM infection, which is one of the mechanisms leading to TM dissemination and chronic persistent infection. In our previously researches, TM can induce the differentiation of Treg cells; promote the increase of IL-10 secretion by Treg cells; and increase the STAT3 phosphorylation in pulmonary macrophages of TM infected mice. It is also reported that STAT3 inhibits iNOS expression and NO synthesis in macrophages, and inhibits IL-6, TNF-α, and IFN-γ. We hypothesized that Treg cells play an important role in the escape mechanism of TM in the host. Based on previous researches, this project will use the mouse model of conditionally knockout IL-10 on Treg cells in vivo study and TM-macrophage-Treg co-culture in vitro study to verify the following hypotheses: Treg cells enhance macrophage phagocytosing TM but inhibit iNOS-NO production of macrophages through IL-10 / JAK1 / STAT3 mediated signaling pathway, thereby reducing the clearance function of macrophages for intracellular TM. The completion of the project will further clarify the host immune regulation mechanism of TM infection and may propose the targeted therapeutic immune intervention in TM infection.