Hodge Greg, Hodge Sandra
Chronic Inflammatory Lung Disease Research Laboratory, Lung Research Unit, Hanson Institute, Adelaide, SA, Australia; Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, SA, Australia; Department of Medicine, University of Adelaide, Adelaide, SA, Australia.
Front Immunol. 2016 Dec 19;7:617. doi: 10.3389/fimmu.2016.00617. eCollection 2016.
Corticosteroid resistance is a major barrier to effective treatment in chronic obstructive pulmonary disease (COPD), and failure to suppress systemic inflammation in these patients may result in increased comorbidity. Although much of the research to date has focused on the role of macrophages and neutrophils involved in inflammation in the airways in COPD, recent evidence suggests that CD8 T cells may be central regulators of the inflammatory network in this disease. CD8 cytotoxic pro-inflammatory T cells have been shown to be increased in the peripheral blood and airways in patients with COPD, whereas smokers that have not progressed to COPD only show an increase in the lungs. Although the mechanisms underlying steroid resistance in these lymphocytes is largely unknown, new research has identified a role for cytotoxic pro-inflammatory CD8 T-cells and CD8 natural killer T-like (NKT-like) cells. Increased numbers of these cells and their significant loss of the co-stimulatory molecule CD28 have been shown in COPD, consistent with findings in the elderly and in clinical conditions involving chronic activation of the immune system. In COPD, these senescent cells expressed increased levels of the cytotoxic mediators, perforin and granzyme b, and the pro-inflammatory cytokines, IFNγ and TNFα. They also demonstrated increased cytotoxicity toward lung epithelial cells and importantly were resistant to immunosuppression by corticosteroids compared with their CD28 counterparts. Further research has shown these cells evade the immunosuppressive effects of steroids multiple mechanisms. This mini review will focus on cytotoxic pro-inflammatory CD8CD28 NKT-like cells involved in COPD and novel approaches to reverse steroid resistance in these cells.
皮质类固醇抵抗是慢性阻塞性肺疾病（COPD）有效治疗的主要障碍，未能抑制这些患者的全身炎症可能导致合并症增加。尽管迄今为止的许多研究都集中在参与COPD气道炎症的巨噬细胞和中性粒细胞的作用上，但最近的证据表明，CD8 T细胞可能是这种疾病炎症网络的核心调节因子。已显示COPD患者外周血和气道中的CD8细胞毒性促炎T细胞增加，而尚未发展为COPD的吸烟者仅在肺部出现增加。尽管这些淋巴细胞中类固醇抵抗的潜在机制很大程度上尚不清楚，但新的研究已经确定了细胞毒性促炎CD8 T细胞和CD8自然杀伤T样（NKT样）细胞的作用。在COPD中已显示这些细胞数量增加且其共刺激分子CD28显著丧失，这与老年人以及涉及免疫系统慢性激活的临床情况中的发现一致。在COPD中，这些衰老细胞表达的细胞毒性介质穿孔素和颗粒酶b以及促炎细胞因子IFNγ和TNFα水平增加。它们还表现出对肺上皮细胞的细胞毒性增加，重要的是与它们的CD28对应物相比，它们对皮质类固醇的免疫抑制具有抗性。进一步的研究表明这些细胞通过多种机制逃避类固醇的免疫抑制作用。本综述将重点关注参与COPD的细胞毒性促炎CD8CD28 NKT样细胞以及逆转这些细胞中类固醇抵抗的新方法。
