Impaired CTLA-4 responses in COPD are associated with systemic inflammation (original) (raw)
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Immunology, 2017
Impaired T helper type 1 (Th1) function is implicated in the susceptibility of patients with chronic obstructive pulmonary disease (COPD) to respiratory infections, which are common causes of acute exacerbations of COPD (AECOPD). To understand the underlying mechanisms, we assessed regulatory T (Treg) cells and the expression of an inhibitory T-cell receptor, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Cryopreserved peripheral blood mononuclear cells (PBMC) from patients with AECOPD (n = 17), patients with stable COPD (sCOPD; n = 24) and age-matched healthy non-smoking controls (n = 26) were cultured for 24 hr with brefeldin-A or monensin to detect intracellular or surface CTLA-4 (respectively) by flow cytometry. T cells in PBMC from AECOPD (n = 9), sCOPD (n = 14) and controls (n = 12) were stimulated with anti-CD3 with and without anti-CTLA-4 blocking antibodies and cytokines were quantified by ELISA. Frequencies of circulating T cells expressing intracellular CTLA-4 were...
Increased intraepithelial T-cells in stable COPD
Respiratory Medicine, 2008
Background: The airway epithelium is the first line of defence in the response to inhaled particles and irritants. Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterised by an irreversible loss of lung function, with cigarette smoking as a major risk factor. Here, we address intraepithelial T-cells in COPD, as these cells are a distinct T-cell subtype thought to have important regulatory functions. We hypothesised that intraepithelial T-cells play a role in the response to lung irritants and that the T-cell populations would be altered and associated with signs of inflammation in COPD. Methods: Bronchoscopy with endobronchial mucosal biopsy sampling was performed in 22 patients (mean age; 57) with stable COPD (median FEV 1 % predicted: 51). Age-and smoking-matched smokers (S) with normal lung function (n Z 14) and age-matched non-smokers (NS) (n Z 15) served as controls. Airway inflammation was recorded visually using bronchitis index (BI). Biopsy specimens were processed into glycol methacrylate resin and inflammatory cells were stained immunohistochemically. Results: The number of intraepithelial CD4þ T-cells were significantly higher in COPD patients compared to smokers as well as trend towards significance in non-smokers (p Z 0.005 and p Z 0.036, respectively), whereas intraepithelial CD8þ T-cells number were increased in patients with COPD compared to non-smokers (p Z 0.017). Both
Lung CD8+ T cells in COPD have increased expression of bacterial TLRs
Respiratory Research, 2013
Background: Toll-like receptors (TLRs) on T cells can modulate their responses, however, the extent and significance of TLR expression by lung T cells, NK cells, or NKT cells in chronic obstructive pulmonary disease (COPD) is unknown. Methods: Lung tissue collected from clinically-indicated resections (n = 34) was used either: (a) to compare the expression of TLR1, TLR2, TLR2/1, TLR3, TLR4, TLR5, TLR6 and TLR9 on lung CD8+ T cells, CD4+ T cells, NK cells and NKT cells from smokers with or without COPD; or (b) to isolate CD8+ T cells for culture with anti-CD3ε without or with various TLR ligands. We measured protein expression of IFN-γ, TNF-α, IL-13, perforin, granzyme A, granzyme B, soluble FasL, CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL9 in supernatants.
Clinical & Experimental Immunology, 2011
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease; it is a leading cause of death and existing treatments have no proven disease-modifying effect. The mechanisms underlying this resistance are largely unknown, but suggest the presence of some self-maintaining pathogenic process, possibly initiated by cigarette smoking, that prevents the normal resolution of inflammation. We have previously reported increased production of proinflammatory cytokines and granzyme b by CD8 + T cells in COPD; costimulatory receptor/ligand interactions required include CD80:86/ CD28, B7-1/CTLA4, 4-1BB/1BBL and OX40/OX40L. We hypothesized that a dysregulated expression/function of these molecules may play a role in inflammatory/autoimmune components of COPD. We analysed T cell co-stimulatory molecules in blood from 34 controls, 15 smokers and 48 COPD subjects. We assessed the potential functional relevance of CD8/ CD28 null cells in COPD by measuring their production of proinflammatory cytokines, co-stimulatory molecules, granzyme and perforin. A smokeexposed murine model was applied to investigate the relative expression of CD8/CD28 null T cells in blood, lung tissue and airway. CD8/CD28 null cells were increased in both current-and ex-smoker COPD groups; these cells expressed significantly more interferon (IFN)-g, OX40, 4-1BB, CTLA4, granzyme and perforin when stimulated than CD8/CD28 + T cells. There were no changes in CD4/CD28 null T cells. In mice exposed to cigarette smoke for 12 weeks, CD8/ CD28 null T cells were significantly increased in the airway with a trend for an increase in lung tissue and blood. Increased production of proinflammatory cytokines and expression of alternative co-stimulatory molecules by CD8/ CD28 null T cells may play a role in inflammatory or autoimmune responses in COPD and identify therapeutic targets.
Clinical & Experimental Immunology, 2007
The role of T cells in the pathophysiology of chronic obstructive pulmonary disease (COPD) is not yet certain, although varying reports have shown increases in T helper 1 (Th1) and/or Th2 cytokines in peripheral blood and bronchoalveolar lavage (BAL). No studies have examined cytokine production by intraepithelial T cells obtained by bronchial brushing (BB). Intracellular cytokine analysis of T cell subsets from peripheral blood, BAL and BB from smoker and ex-smoker COPD patients, COPD patients receiving inhaled corticosteroids and smoker and non-smoker control subjects was studied using multi-parameter flow cytometry. CD4 : CD8 inversion was noted in the peripheral blood of smoker and ex-smoker COPD groups, in BAL and BB from smoker controls and BAL of COPD smokers. There was an increase in intracellular CD8 + T cell Th1 proinflammatory cytokines in some COPD groups in the peripheral blood and in CD8 + T cell tumour necrosis factor (TNF)-a in some COPD groups and smoker controls in BAL and BB. There was an increase in proinflammatory cytokines in COPD smokers compared with ex-smokers and a decrease in COPD smokers receiving inhaled corticosteroids in the airways. There was a negative correlation between forced expiratory volume in 1 s (FEV1) and the percentage of BAL and intraepithelial CD8 + T cells producing TNF-a. COPD patients exhibit systemic inflammation as evidenced by increased intracellular Th1 proinflammatory cytokines in blood, BAL and intraepithelial CD8 + T cells, whereas smoker controls showed localized Th1 response in the lung only. Systemic therapeutic targeting of TNF-a production by CD8 + T cells may improve morbidity in COPD patients while targeting of TNF-a in the lung may prevent smokers progressing to COPD.
Immunobiology, 2014
Anti-inflammatory pathways affecting chronic obstructive pulmonary disease (COPD) are poorly understood. Regulatory T-cells (Tregs) are important negative regulators of T-cell activity and hence were investigated in COPD patients in this study. We hypothesised that functional defects in Tregs may promote increased inflammation contributing to the pathogenesis of COPD. Peripheral blood mononuclear cells (PBMC) were isolated from patients with stable COPD and age-matched non-smoking controls. Treg-mediated suppression of memory non-Treg (Foxp3(-)CD45RO(+)) CD4(+) T-cell activation was analysed by comparing PBMC responses to staphylococcal enterotoxin-B (SEB) pre- and post-depletion of Tregs (CD25(+)CD127(low)CD4(+) T-cells) by fluorescence-activated cell sorting (FACS). Activation of T-cells was assessed by HLA-DR expression. Levels of secreted cytokines were measured by ELISA. Depletion of Tregs increased SEB-induced activation of Foxp3(-)CD45RO(+) CD4(+) T-cells in samples from 15/1...
Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG / World Association of Sarcoidosis and Other Granulomatous Disorders, 2003
The presence of a heterogeneous infiltrate of macrophages, neutrophils and CD8+ Tc1 cells is a characteristic feature in the lung of patients with chronic obstructive pulmonary disease (COPD). This paper points out the contribution of different inflammatory cells and mediators to the pathogenesis and natural history of COPD. We will comment on data suggesting that CD8 cytotoxic T cells with an activated Tc1 phenotype migrate from the secondary lymphoid tissue to pulmonary tissue damaged by smoke or infective agents. On the basis of the knowledge of the pathophysiology of immunologic events, drugs that can potentially block the inflammation leading to the disability of COPD are being investigated. Long-term study in a large number of patients with COPD will be needed to verify the impact of a number of anti-inflammatory compounds in this increasingly common disease.
Advances in Respiratory Medicine
Introduction: Many theories have been proposed to explain pathogenesis of COPD; however, remains unclear why the majority of smokers (~80%) do not develop COPD, or only develop a mild disease. To explore if COPD has an autoimmune component, the role of T regulatory lymphocytes (Tregs) in the lung tissue of COPD patients is of crucial importance. Material and methods: Bronchial tissue biopsy samples were prospectively collected from 64 patients (39 COPD and 25 controls-15 smokers and 10 non-smokers). The patients with COPD were subdivided into mild/moderate (GOLD stage I−II) and severe/very severe (GOLD stage III−IV) groups. Digital image analysis was performed to estimate densities of CD4+ CD25+ cell infiltrates in double immunohistochemistry slides of the biopsy samples. Blood samples were collected from 42 patients (23 COPD and 19 controls) and tested for CD3+ CD4+ CD25+ bright lymphocytes by flow cytometry. Results: The number of intraepithelial CD4+ CD25+ lymphocytes mm-2 epithelium was significantly lower in the severe/very severe COPD (GOLD III-IV) group as well as in the control non-smokers (NS) group (p < 0,0001). Likewise, the absolute number of Treg (CD3+ CD4+ CD25+ bright) cells in the peripheral blood samples was significantly different between the four groups (p = 0.032). The lowest quantity of Treg cells was detected in the severe/very severe COPD and healthy non-smokers groups. Conclusion: Our findings suggest that severe COPD is associated with lower levels of Tregs in the blood and bronchial mucosa, while higher Tregs levels in the smokers without COPD indicate potential protective effect of Tregs against developing COPD.
Respiratory Research, 2011
Background: Cigarette smoke is a major risk factor for chronic obstructive pulmonary disease (COPD), an inflammatory lung disorder. COPD is characterized by an increase in CD8 + T cells within the central and peripheral airways. We hypothesized that the CD8 + T cells in COPD patients have increased Toll-like receptor (TLR) expression compared to control subjects due to the exposure of cigarette smoke in the airways. Methods: Endobronchial biopsies and peripheral blood were obtained from COPD patients and control subjects. TLR4 and TLR9 expression was assessed by immunostaining of lung tissue and flow cytometry of the peripheral blood. CD8 + T cells isolated from peripheral blood were treated with or without cigarette smoke condensate (CSC) as well as TLR4 and TLR9 inhibitors. PCR and western blotting were used to determine TLR4 and TLR9 expression, while cytokine secretion from these cells was detected using electrochemiluminescence technology. Results: No difference was observed in the overall expression of TLR4 and TLR9 in the lung tissue and peripheral blood of COPD patients compared to control subjects. However, COPD patients had increased TLR4 and TLR9 expression on lung CD8 + T cells. Exposure of CD8 + T cells to CSC resulted in an increase of TLR4 and TLR9 protein expression. CSC exposure also caused the activation of CD8 + T cells, resulting in the production of IL-1β, IL-6, IL-10, IL-12p70, TNFα and IFNγ. Furthermore, inhibition of TLR4 or TLR9 significantly attenuated the production of TNFα and IL-10. Conclusions: Our results demonstrate increased expression of TLR4 and TLR9 on lung CD8 + T cells in COPD. CD8 + T cells exposed to CSC increased TLR4 and TLR9 levels and increased cytokine production. These results provide a new perspective on the role of CD8 + T cells in COPD.