Swiprosin-1在脓毒症中调控T细胞免疫抑制的作用及机制研究

Most of the patients who died of sepsis presented a state of immunosuppression. The inhibition of T cell immune function is the key to the development of sepsis, and the function of the immunological synapse in the hypo-response T cells is impaired. We have found that swiprosin-1 plays an important role in the activation of macrophages in the early stage of sepsis. Meanwhile, the deletion of swiprosin-1 can lead to the reduction of cause the function of IFN gamma released by T cells. Therefore, we speculate that swiprosin-1 may also be involved in the immune activation of T cells in sepsis. Functionally, swiprosin-1 is associated with lipid rafts and the reorganization of cytoskeleton, which are the key elements of the formation of immunological synapse. We hypothesized that, with the development of sepsis, the expression of swiprosin-1 in T cells is down regulated, which interferes with lipid rafts and cytoskeletal remodeling, resulting in immune synapse defects and T cell-immunosuppression. To prove this conjecture, we plan to construct two genetically engineered mice that specifically knock out or knock in swiprosin-1 in T cells, and clarify the role of swiprosin-1 in the T cells-immunosuppression of sepsis. In vitro, we intend to investigate the role and mechanism of swiprosin-1 to regulate the formation of immunological synapse in the T cell and macrophage co-culture model. Finally, the expression of swiprosin-1 will be induced to evaluate its therapeutic effect in the immunosuppression of T cell in sepsis.This study is expected to provide a new potential target for the immunomodulation of T cells in sepsis. Therefore, this research is needed in urgent.

临床上死于脓毒症的患者多表现为免疫抑制。T细胞免疫功能抑制是脓毒症发展的关键，而低应答状态的T细胞形成免疫突触的功能受损。我们前期发现swiprosin-1（Swip）在脓毒症巨噬细胞的激活中发挥作用。同时，Swip的缺失导致T细胞分泌的IFNγ减少。因此，Swip可能也参与脓毒症中T细胞的免疫激活。Swip与脂筏和细胞骨架的构成相关，而这两者正是免疫突触形成的关键。于是，我们假设：随着脓毒症的进展，T细胞Swip表达下调，干扰脂筏和细胞骨架重构，造成免疫突触缺陷和T细胞抑制。为证明猜想，拟构建T细胞特异性敲除或诱导Swip基因工程小鼠，明确T细胞中Swip在脓毒症免疫抑制中的作用；在T细胞和巨噬细胞共培养模型中考察Swip调控免疫突触形成的作用和机制；最后诱导Swip的表达以评价其在脓毒症T细胞免疫抑制中的治疗作用。该项目将有望为脓毒症T细胞免疫调理提供新的潜在靶点，具有重要的研究价值。

脓毒症是机体对感染的反应失调而导致危及生命的器官功能障碍。其中，机体在脓毒症时发生严重免疫紊乱是反应失调的核心环节。越来越多的证据表明免疫抑制是脓毒症的重要致病因素，且临床上死于脓毒症的患者也多表现为严重的免疫抑制。T细胞的功能缺陷可以用来反映脓毒症诱导的免疫抑制，但是其调控的分子机制尚不清楚。T细胞的免疫识别和激活依赖于免疫突触，而免疫突触的形成是在脂筏区域内依托细胞骨架组装而完成。脂筏相关蛋白swiprosin-1在T细胞中参与调控细胞骨架F-actin的聚合，因此本项目设想：脓毒症中T细胞swiprosin-1表达下调，干扰T细胞脂筏稳定和细胞骨架重构，导致免疫突触形成受阻，造成T细胞免疫功能衰减，最终加重机体的免疫抑制。本项目主要研究内容包括三个方面：（1）swiprosin-1的缺失对脓毒症免疫抑制和T细胞免疫失调的作用；（2）swiprosin-1的缺失造成T细胞免疫抑制的机制；（3）调控swiprosin-1表达改善脓毒症免疫抑制和T细胞免疫失调的作用。研究发现：（1）swiprosin-1在介导脓毒症T细胞免疫活化中发挥重要作用，主要表现为swiprosin-1缺失导致脓毒症诱导的T细胞激活、增殖和分化功能受损。（2）机制上，这可能与swiprosin-1参与T细胞活化时免疫突触的形成和IL-2受体在脂筏中的功能性聚合相关。（3）脓毒症早期T细胞中swiprosin-1表达被诱导，但是随着病程进展会出现T细胞中swiprosin-1表达水平下调，这可能是造成脓毒症后期T细胞免疫抑制的关键所在。本研究围绕swiprosin-1调控脓毒症中T细胞免疫抑制为核心开展系统研究，初步明确swiprosin-1作为脓毒症中T细胞免疫抑制调控的潜在靶点及其分子作用机制，为进一步开展脓毒症免疫调理策略的研究提供理论基础。