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T cells in chronic obstructive pulmonary disease
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. (Lungmedicin)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Tobacco smoking is the main cause of chronic obstructive pulmonary disease, COPD, but the mechanisms by which cigarette smoke induces COPD are still elusive. T lymphocytes have been implicated in the pathogenesis of the disease, but their role in the airway inflammation in COPD is not fully understood. The aim of this thesis was therefore to address T lymphocyte subsets and their activation in the airways of subjects with COPD, in comparison to smokers with normal lung function (S) and never smokers (NS).

Methods: Subjects with moderate to severe COPD were recruited along with controls. They were all non-atopic and clinically stable, without any exacerbation during at least three months prior to inclusion. Only medication with short-acting β2-agonists and/or anti-cholinergic drugs was permitted. All subjects underwent bronchoscopy with endobronchial mucosal biopsy sampling as well as bronchial wash, BW, and bronchoalveolar lavage, BAL, collection. Biopsies were immunohistochemically stained for inflammatory cells and markers. BW and BAL fluids were prepared for differential cell counts. Soluble markers were measured in BW and lymphocyte subsets were determined in BAL using flow cytometry.

Results: In biopsies, an increase in epithelial CD3+ and CD8+ cells was found in COPD, compared to NS. In BAL fluid, CD8+ cells were enhanced, whereas CD4+ cells were reduced in subjects with COPD and S, compared to NS. Furthermore, CD4+ and CD8+ cells were more activated both in COPD and S, in terms of increased expression of CD25, CD69 and HLA-DR. NKG2D-expressing CD8+ T cells in BAL fluid were enhanced in both COPD and S. CD4+CD25bright cells were upregulated in COPD and S, suggesting the presence of regulatory T cells. Further analyses of T cell subsets with the more specific markers for regulatory T cells, FoxP3 and CD127, indicated a smoking-induced expansion of non-regulatory T cells, which tended to normalize after smoking cessation in COPD. Currently smoking subjects with COPD still expressed high proportions of activated non-regulatory CD4+ T cells. The data on FoxP3 expression further indicated that the increase in CD25 expression in COPD and S was not only associated with the expansion of regulatory T cells. As CD127 expression is reported to be inversely associated with FoxP3, the data indicate the expansion of a non-regulatory CD25+ population in smokers and patients with stable COPD. The immunohistochemical staining for the NKG2D ligands MICA and MICB on epithelial cells was unchanged.

Conclusion: The results of this thesis suggest a role for CD4+ and CD8+ T-cells in clinically stable COPD, indicating that T-cells are of importance in the long-term inflammatory response in COPD. Regardless of current smoking habits, activated CD8+ T lymphocytes were found to be increased in BAL fluid from subjects with COPD, suggesting that changes in CD8+ T cells are associated with a persistent immune response and, thus, of importance in COPD pathogenesis. In contrast, the expansion of non-regulatory CD25+CD4+ cells in BAL fluid seemed to be preferentially smoke-related. In summary, the data indicate that, among airway T cells, changes in CD8+ cells seem to be highly associated with COPD pathogenesis, whereas changes in CD4+ cells appear to be related to cigarette smoke-induced responses. Further, a non regulatory population of helper T cells was identified in BAL fluid of COPD patients, which may contribute to the persistent cytotoxic T cell responses.

Place, publisher, year, edition, pages
Umeå: Umeå university , 2010. , 86 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1331
Keyword [en]
airway epithelium, bronchoscopy, bronchoalveolar lavage, endobronchial mucosal biopsies, inflammation, flow cytometry, T lymphocytes, CD25, CD127, FoxP3
National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine
Identifiers
URN: urn:nbn:se:umu:diva-33677ISBN: 978-91-7264-952-1 (print)OAI: oai:DiVA.org:umu-33677DiVA: diva2:317196
Public defence
2010-06-04, Betula, Byggnad 6M, NUS, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2010-05-15 Created: 2010-05-03 Last updated: 2010-08-26Bibliographically approved
List of papers
1. Increased intraepithelial T-cells in stable COPD
Open this publication in new window or tab >>Increased intraepithelial T-cells in stable COPD
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2008 (English)In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 102, no 12, 1812-1818 p.Article in journal (Refereed) Published
Abstract [en]

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=14) and age-matched non-smokers (NS) (n=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 CD4+ T-cells were significantly higher in COPD patients compared to smokers as well as trend towards significance in non-smokers (p=0.005 and p=0.036, respectively), whereas intraepithelial CD8+ T-cells number were increased in patients with COPD compared to non-smokers (p=0.017). Both patients with COPD and smokers had a higher BI than non-smokers (p<0.001 for both).

CONCLUSIONS: The present data suggest a role for intraepithelial CD4+ and CD8+ T-cells in stable COPD and indicate that T-cells are of importance in the long-term inflammatory response in COPD or, alternatively, play a regulatory role.

National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine
Identifiers
urn:nbn:se:umu:diva-19130 (URN)10.1016/j.rmed.2008.06.013 (DOI)18706796 (PubMedID)
Available from: 2009-03-04 Created: 2009-03-04 Last updated: 2010-08-26Bibliographically approved
2. Influence of smoking cessation on airway T lymphocyte subsets in COPD
Open this publication in new window or tab >>Influence of smoking cessation on airway T lymphocyte subsets in COPD
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2009 (English)In: COPD, ISSN 1541-2563, Vol. 6, no 2, 112-120 p.Article in journal (Refereed) Published
Abstract [en]

The mechanisms behind airway inflammation in chronic obstructive pulmonary disease (COPD) are still not well understood. Here we investigated lymphocyte subtypes in bronchoalveolar lavage fluid, likely to be involved in the pathogenesis of COPD, as well as exploring the effect of smoking cessation. Differential cell counts and T cell subsets were determined in BAL fluid from nineteen individuals with stable COPD (seven smokers, twelve ex-smokers) compared to twelve age-matched never-smokers and thirteen smoking-matched smokers with normal lung function. COPD-patients had higher percentages of airway CD8(+) T cells compared to never-smokers. An increased population of CD4(+) T cells expressed high levels of CD25 in smokers and COPD patients compared to never-smokers, suggesting the presence of regulatory T cells. As the T cell populations in smokers with normal lung function and COPD-patients were similar, the impact of current smoking in COPD was addressed in a subgroup analysis. Activation of CD8(+) T cells was found regardless of smoking habits. In contrast, the enhanced expression of gamma/delta T cells, was mainly associated with current smoking, whilst the increase in T regulatory cells appeared related to both smoking and COPD. Regardless of smoking habits, CD8(+) T cell activation was found in COPD, supporting the contention that this T cell subset may play a role in the pathogenesis of COPD. As CD8(+) T cells coexist with immunoregulatory CD4(+) T cells in airways of COPD patients, it is likely that both cytotoxic T-cell responses and immunosuppressive mechanisms may be of importance in COPD pathogenesis.

National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine
Identifiers
urn:nbn:se:umu:diva-31036 (URN)10.1080/15412550902755358 (DOI)19378224 (PubMedID)
Available from: 2010-01-27 Created: 2010-01-27 Last updated: 2010-08-26Bibliographically approved
3. Expansion of helper T cells with a non-regulatory function in smoking and COPD
Open this publication in new window or tab >>Expansion of helper T cells with a non-regulatory function in smoking and COPD
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Regulatory T cells have been implicated in the pathogenesis of COPD by the increased expression of CD25 on helper T cells. Regulatory CD4+ T cells are reported to have increased intracellular expression of FoxP3 and low/absent CD127 expression on the cell surface. Here, these markers were investigated in BALF from nine COPD subjects and compared to fourteen smokers with normal lung function and nine never-smokers.

In smokers with normal lung function, the expression of CD25 on CD4+ lymphocytes was increased, whereas the proportions of FoxP3+ and CD127+ were unchanged compared to never-smokers. Among the population of helper T cells expressing high levels of CD25, the proportion FoxP3+ cells was decreased and the percentage CD127+ was increased in smokers with normal lung function. CD25+ helper T cells with low/absent CD127 expression were increased in smokers with normal lung function, but not in COPD, when compared to never smokers. In COPD, a decrease in CD127 expression on CD4+CD25+ was observed in ex-smokers compared to current smokers.

Smoking induces the expansion of activated airway helper T cells that seem to persist after COPD development. The reduction of FoxP3 expression indicates that the increase in CD25 expression is not only associated with the expansion of regulatory T cells. Instead, the high CD127 and low FoxP3 expressions implicate a predominantly non-regulatory CD25+ helper T cell population in stable COPD. In some smokers with normal lung function, we identified a helper T cell population with a putative regulatory function, which may be protective against COPD development.

National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine
Identifiers
urn:nbn:se:umu:diva-33670 (URN)
Available from: 2010-05-03 Created: 2010-05-03 Last updated: 2010-05-15Bibliographically approved
4. Cytotoxic T cells expressing the co-stimulatory receptor NKG2D are increased in cigarette smoking and COPD
Open this publication in new window or tab >>Cytotoxic T cells expressing the co-stimulatory receptor NKG2D are increased in cigarette smoking and COPD
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2010 (English)In: Respiratory research (Online), ISSN 1465-993X, Vol. 11, 128- p.Article in journal (Refereed) Published
Abstract [en]

Background: A suggested role for T cells in COPD pathogenesis is based on associations between increased lung cytotoxic T lymphocyte (CD8+) numbers and airflow limitation. CD69 is an early T cell activation marker. NKG2D receptors are co-stimulatory molecules induced on CD8+ T cells upon activation. The activating function of NKG2D is triggered by binding to the MHC class 1 chain-related (MIC) molecules A and B, expressed on surface of stressed epithelial cells. The aim of this study was to evaluate the expression of MIC A and B in the bronchial epithelium and NKG2D and CD69 on BAL lymphocytes in subjects with COPD, compared to smokers with normal lung function and healthy never-smokers.

Methods: Bronchoscopy with airway lavages and endobronchial mucosal biopsy sampling was performed in 35 patients with COPD, 21 healthy never-smokers and 16 smokers with normal lung function. Biopsies were immunohistochemically stained and BAL lymphocyte subsets were determined using flow cytometry.

Results: Epithelial CD3+ lymphocytes were increased in both smokers with normal lung function and in COPD patients, compared to never-smokers. Epithelial CD8+ lymphocyte numbers were higher in the COPD group compared to never-smoking controls. Among gated CD3+cells, the percentage of CD8+ NKG2D+ cells was enhanced in patients with COPD and smokers with normal lung function, compared to never-smokers. The percentage of CD8+ CD69+ cells and cell surface expression of CD69 were enhanced in patients with COPD and smokers with normal lung function, compared to never-smokers. No changes in the expression of MIC A or MIC B in the airway epithelium could be detected between the groups, whereas significantly decreased soluble MICB was detected in bronchial wash from smokers with normal lung function, compared to never-smokers.

Conclusions: In COPD, we found increased numbers of cytotoxic T cells in both bronchial epithelium and airway lumen. Further, the proportions of CD69- and NKG2D-expressing cytotoxic T cells in BAL fluid were enhanced in both subjects with COPD and smokers with normal lung function and increased expression of CD69 was found on CD8+ cells, indicating the cigarette smoke exposure-induced expansion of activated cytotoxic T cells, which potentially can respond to stressed epithelial cells.

National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine
Identifiers
urn:nbn:se:umu:diva-33673 (URN)10.1186/1465-9921-11-128 (DOI)000282985300001 ()20863413 (PubMedID)
Available from: 2010-05-03 Created: 2010-05-03 Last updated: 2012-01-10Bibliographically approved

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