抑制天然免疫系统过度活化导致的"细胞因子风暴"，是脓毒症免疫治疗研究的重点。最近发现：T淋巴细胞可通过细胞直接接触抑制天然免疫细胞过度分泌细胞因子，但机制不清。既往认为共抑制分子PD-1主要调控获得性免疫应答。申请人前期工作发现：抗PD-1抗体和抗PD-L1抗体可逆转T 细胞对天然免疫细胞分泌细胞因子的抑制作用，并且感染可迅速上调PD-1及其配体PD-L1在天然免疫细胞的表达水平，由此提出："PD-1/PD-L1是脓毒症时抑制天然免疫应答的重要信号通路"。我们拟采用体外和体内实验，证实PD-1/PD-L1通过 1）参与T 淋巴细胞抑制天然免疫应答；2）参与天然免疫自身负反馈调控，抑制天然免疫细胞分泌炎性细胞因子；阐明天然免疫细胞内PD-1/PD-L1的下游信号通路，将PD-1/PD-L1这一重要免疫调节通路的关注点，由获得性免疫应答延伸到天然免疫应答领域，推动脓毒症的临床免疫治疗研究。

One of the major strategies of immunotherapy of sepsis is tempering "cytokine storm" which is induced by over-activation of innate immune response. Recent studies revealed that T lymphocytes could dampen cytokine secretion by innate immune cells in a cell-cell contact manner. However, the mechanisms remain unclear. PD-1 (programmed death-1), a co-inhibitory molecule was well recognized as a key regulator of adaptive immune response. Our previous study found that neutralizing antibodies of PD-1 and PD-L1 could reverse the inhibitory effect of T cells on cytokine secretion by innate immune cells. Meanwhile, an increase of both PD-1 and PD-L1 expression was noted on innate immune cells after infection. Thus, we suppose that PD-1/PD-L1 might play a key role in inhibiting innate immune response during sepsis. To test this hypothesis, we intend to perform in vitro and in vivo experiments to investigate the role of PD-1/PD-L1 in negative regulation of innate immunity, either by T cells or self feedback regulation of innate immunity. Moreover, we will clarify the downstream signalling pathways of PD-1/PD-L1 in innate immune cells. Our study would expand our knowledge about PD-1/PD-L1 from adaptive immune response to innate immune response, and promote clinic immune therapy research for sepsis.