Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients.
Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients.
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DOI：
10.1186/cc14003
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发表时间：
2014-08-01
期刊：
影响因子：
--
通讯作者：
Woodberry T
中科院分区：
文献类型：
--
作者：
Darcy CJ;Minigo G;Piera KA;Davis JS;McNeil YR;Chen Y;Volkheimer AD;Weinberg JB;Anstey NM;Woodberry T
脓毒症患者T细胞功能受损与预后不良相关，但其机制尚不清楚。在癌症中，表达精氨酸酶的髓源性抑制细胞（MDSC）消耗精氨酸，损害T细胞受体CD 3 ζ链表达和T细胞功能，并且与不良临床结果相关，但它们在急性人类感染性疾病，特别是脓毒症期间的作用仍然未知。败血症中普遍存在低血糖。本研究旨在确定与PBMC共纯化的中性粒细胞是否表达精氨酸酶，以及精氨酸耗竭是否抑制人脓毒症中T细胞CD 3 ζ链的表达和功能。使用流式细胞术，细胞培养，HPLC，胰蛋白酶活性和mRNA检测，我们的研究检查是否中性粒细胞，减少浮力密度分离在Ficoll接口，代谢L-精氨酸和抑制T细胞增殖脓毒症。在澳大利亚热带地区的一家三级转诊医院，共对35例脓毒症患者（23例脓毒性休克）和12例医院对照进行了评价。仅脓毒症患者有间期中性粒细胞，中性粒细胞与单核细胞共纯化（比重≤1.077）。脓毒症间期中性粒细胞的百分比与脓毒症的严重程度成正比，并与血浆IL-6浓度相关。离体，脓毒症衍生的间期中性粒细胞表达凝血酶，代谢培养L-精氨酸，抑制T细胞增殖和CD 3 ζ链表达。在体内，在感染性休克中，间期中性粒细胞数量和CD 3 ζ链表达之间存在纵向负相关。在体外消耗或抑制间期中性粒细胞恢复zeta链表达和T细胞功能。首次在急性人类感染期间，发现表达β-内酰胺酶的间期中性粒细胞在脓毒症中循环，与疾病严重程度成比例。这些嗜中性粒细胞-MDSC通过L-精氨酸代谢损害T细胞CD 3 ζ链表达和T细胞功能，并可能导致脓毒症中观察到的T细胞功能障碍。调节嗜中性粒细胞-MDSC或其下游作用值得考虑作为脓毒症中新的预防性治疗的靶点。本文的在线版本（doi：10.1186/cc 14003）包含补充材料，可供授权用户使用。
Impaired T cell function in sepsis is associated with poor outcome, but the mechanisms are unclear. In cancer, arginase-expressing myeloid derived suppressor cells (MDSCs) deplete arginine, impair T cell receptor CD3 zeta-chain expression and T cell function and are linked to poor clinical outcome, but their role during acute human infectious disease and in particular sepsis remains unknown. Hypoarginemia is prevalent in sepsis. This study aimed to determine whether neutrophils that co-purify with PBMC express arginase, and if arginine depletion constrains T cell CD3 zeta-chain expression and function in human sepsis. Using flow cytometry, cell culture, HPLC, arginase activity and mRNA detection, our study examined whether neutrophils, with reduced buoyant density isolated in the Ficoll interface, metabolise L-arginine and suppress T cell proliferation in sepsis. A total of 35 sepsis patients (23 with septic shock) and 12 hospital controls in a tertiary referral hospital in tropical Australia were evaluated. Only sepsis patients had interphase neutrophils, neutrophils co-purifying with mononuclear cells (≤1.077 specific gravity). The percentage of interphase neutrophils in sepsis was proportional to sepsis severity and correlated with plasma IL-6 concentrations. Ex vivo, sepsis-derived interphase neutrophils expressed arginase, metabolised culture L-arginine and suppressed T cell proliferation and CD3 zeta-chain expression. In vivo, in septic shock there was a longitudinal inverse association between interphase neutrophil number and CD3 zeta-chain expression. Depletion or inhibition of interphase neutrophils in vitro restored zeta-chain expression and T cell function. For the first time during an acute human infection, interphase neutrophils that express arginase were found to circulate in sepsis, in proportion to disease severity. These neutrophil-MDSCs impair T cell CD3 zeta-chain expression and T cell function via L-arginine metabolism, and likely contribute to the T cell dysfunction seen in sepsis. Modulation of neutrophil-MDSC or their downstream effects warrant consideration as targets for novel adjunctive therapies in sepsis. The online version of this article (doi:10.1186/cc14003) contains supplementary material, which is available to authorized users.
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影响因子：
6.4
作者：
Garg, Ankita;Spector, Stephen A.
通讯作者：
Spector, Stephen A.
DOI：
10.4049/jimmunol.1000901
发表时间：
2010-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lechner MG;Liebertz DJ;Epstein AL
通讯作者：
Epstein AL
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
11.2
作者：
Bunt, Stephanie K.;Yang, Linglin;Ostrand-Rosenberg, Suzanne
通讯作者：
Ostrand-Rosenberg, Suzanne
影响因子：
4.1
作者：
Kong, Y. Y.;Fuchsberger, M.;Plebanski, M.
通讯作者：
Plebanski, M.