Trem2在抑制肺孢子菌肺炎（PCP）宿主CD4+T细胞过度免疫应答中的作用及机制研究

随免疫抑制手段广泛应用，PCP发病率逐年上升，是患者死亡的重要病因。过度T细胞免疫是重症PCP相关严重病理损伤的主要原因。我们前期发现小鼠PC感染后肺泡巨噬细胞Trem2表达升高，并促进巨噬细胞IL-10分泌，抑制CD4+T细胞增殖。文献报道Trem2通过DAP12-Syk促进吞噬及抑制炎症。据此，我们提出假说：Trem2识别PC通过DAP12-Syk激活促进对病原体吞噬清除；同时促进IL-10分泌、抑制CD4+T细胞应答（增殖和分化），减轻肺组织损伤。项目拟使用Trem2-/-小鼠构建PC感染模型，探究Trem2对T细胞应答和肺部损伤的影响，明确DAP12-Syk通路作用；同时探讨IL-10是否是Trem2+巨噬细胞抑制T细胞免疫的关键细胞因子。项目重点阐述Trem2对PCP中CD4+T细胞免疫调节及其可能机制，拟为重症PCP治疗提供新靶点。

With the development of immunosuppressive treatments, the incidence of PCP is increasing. Excessively activation of T cells can cause serious pathological damage in severe PCP patients. Therefore, it is urgent to explore new method in order to suppress excessive T cell response. Previous results show that Trem2 receptor expressed on alveolar macrophages increases rapidly after mice PC infection. What’s more, Trem2+ macrophages secrete higher IL-10 and inhibit the proliferation of CD4+ T cells. It is reported that Trem2 promotes phagocytosis and anti-inflammatory cytokine secretion through DAP12-Syk pathway. Given that, we hypothesis that: During PC invasion, Trem2 receptor recognizes PC and promotes phagocytosis and clearance of pathogens through the DAP12-Syk pathway; at the same time, it induces IL-10 secretion and inhibits proliferation as well as differentiation of CD4+ T cells. We intend to further explore the effect of Trem2 on T cells response and lung injury, clarify the role of DAP12-Syk pathway and explore whether IL-10 is the inhibitor of T cell immunity via the model of infectious Trem2-/- mice. This research mainly focuses on the immunoregulatory role of Trem2 on CD4+ T cells during PC infection and its possible mechanism.