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      Peripheral blood CD4+ T cell populations by CD25 and Foxp3 expression as a potential biomarker: reflecting inflammatory activity in chronic obstructive pulmonary disease

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          The temporally dynamic changes of CD25 and Foxp3 expression in CD4+ T cells are initiated by T cell receptor (TCR) signals strength or frequency. There is a deficiency of peripheral markers for assessing COPD activity, and the current study was conducted to explore whether peripheral CD4+ T cell populations based on CD25 and Foxp3 expression could serve as an indicator for COPD inflammatory activity.


          The distribution and phenotypic characteristics of CD4+CD25±Foxp3± T cells from peripheral blood in different populations were determined by flow cytometry. The model for the differentiation of CD4+ T cells populations by CD25 and Foxp3 expression was explored in vitro.


          The frequencies of peripheral CD4+CD25+Foxp3− T cells and CD4+CD25+Foxp3+ T cells were increased in AECOPD patients, whereas the frequency of CD4+CD25−Foxp3+ T cells was increased in SCOPD patients without receiving systemic treatment. Phenotypic analysis revealed that CD4+CD25+Foxp3− T cells, CD4+CD25+Foxp3+ T cells and CD4+CD25−Foxp3+ T cells had received antigenic stimulation and resembled central memory or effector memory T cells. The differentiation of CD4+ T cells populations by CD25 and Foxp3 expression was dictated by TCR signals. The paired study indicated that the frequencies of CD4+CD25+Foxp3− T cells, CD4+CD25+Foxp3+ T cells and CD4+CD25− Foxp3+ T cells were decreased while the frequency of CD4+CD25−Foxp3− T cells were increased in the same patients from AECOPD to convalescence.


          Collectively, we propose that the dynamic changes of CD4+ T cell populations by CD25 and Foxp3 expression could function as potential biomarkers for reflecting inflammatory activity in COPD.

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          Most cited references 23

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          Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells.

          Foxp3 plays a key role in CD4+ CD25+ T(reg) cell function in mice and represents a specific marker for these cells. Despite the strong association between FOXP3 expression and regulatory function in fresh human T cells, little is known about the dynamics of endogenous FOXP3 expression and its relation to the suppressive function in activated human T cells. Here, we addressed the dynamics of FOXP3 expression during human CD4+ T cell activation by plate-bound anti-CD3 Ab as well as the relationship between its expression and regulatory function at the single-cell level. Our data show that FOXP3 is expressed in a high percentage of activated T cells after in vitro stimulation of human CD4+ CD25- cells. FOXP3 expression is strongly associated with hyporesponsiveness of activated T cells, but is not directly correlated with their suppressive capabilities, as we demonstrate that it is also expressed in activated nonsuppressive T cells. However, in this nonsuppressive T cell population, FOXP3 expression is transient, while it is stably expressed in activated T cells that do display suppressive function, and in natural CD4+ CD25++ T(reg) cells. These data indicate that expression of endogenous FOXP3, in humans, is not sufficient to induce regulatory T cell activity or to identify T(reg) cells.
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            Pathogenesis of chronic obstructive pulmonary disease.

            The current epidemic of chronic obstructive pulmonary disease (COPD) has produced a worldwide health care burden, approaching that imposed by transmittable infectious diseases. COPD is a multidimensional disease, with varied intermediate and clinical phenotypes. This Review discusses the pathogenesis of COPD, with particular focus on emphysema, based on the concept that pulmonary injury involves stages of initiation (by exposure to cigarette smoke, pollutants, and infectious agents), progression, and consolidation. Tissue damage entails complex interactions among oxidative stress, inflammation, extracellular matrix proteolysis, and apoptotic and autophagic cell death. Lung damage by cigarette smoke ultimately leads to self-propagating processes, resulting in macromolecular and structural alterations - features similar to those seen in aging.
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              Systemic inflammation and comorbidity in COPD: a result of 'overspill' of inflammatory mediators from the lungs? Review of the evidence.

              Chronic obstructive pulmonary disease (COPD) is characterised by an inflammatory response by the lungs to inhaled substances such as cigarette smoking and air pollutants. In addition to the pulmonary features of COPD, several systemic effects have been recognised even after controlling for common aetiological factors such as smoking or steroid use. These include skeletal muscle dysfunction, cardiovascular disease, osteoporosis and diabetes. Individuals with COPD have significantly raised levels of several circulating inflammatory markers indicating the presence of systemic inflammation. This raises the issue of cause and effect. The role of tumour necrosis factor α in COPD is thought to be central to both lung and systemic inflammation and has been implicated in skeletal muscle dysfunction, osteoporosis and type 2 diabetes. It has been hypothesised that inflammation in the lung results in 'overspill' into the circulation causing systemic inflammation. There is supportive evidence that protein movement can occur from the lung surface to the systemic circulation. Evidence from inhaled substances such as air pollutants and cigarette smoke has demonstrated a temporal link between the inflammatory process in the lung and systemic inflammation. Also, studies have shown alterations in circulating inflammatory cells in patients with COPD compared with controls which may reflect the effects of inflammatory mediators (derived from the lung) on circulating cells or the bone marrow. This paper considers the concept of 'overspill' in depth, reviews the current evidence and highlights problems in generating direct evidence to support or refute this concept.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of Chronic Obstructive Pulmonary Disease
                30 July 2019
                : 14
                : 1669-1680
                [1 ]Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, People’s Republic of China
                Author notes
                Correspondence: Xian-Zhi XiongDepartment of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Jiefang Avenue 1277, Wuhan, Hubei430022, People’s Republic of ChinaEmail xxz0508@

                These authors contributed equally to this work

                © 2019 Meng et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (

                Page count
                Figures: 4, Tables: 1, References: 35, Pages: 12
                Original Research

                Respiratory medicine

                copd, cd4+ t cell subsets, inflammation, peripheral biomarkers


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