T cell senescence and contraction of T cell repertoire diversity in patients with chronic obstructive pulmonary disease.
Pathogenetic mechanisms leading to chronic obstructive pulmonary disease (COPD) remain poorly understood. Because clonogenic T cells (CD4(+)CD28(null)) were shown to be increased in autoimmune diseases we hypothesized that CD4(+)CD28(null) T cells play a role in COPD. Here we describe that enhanced presence of CD4(+)CD28(null) cells is associated with impaired lung function. Sixty-four patients and controls were included. T cell phenotype was analysed using flow cytometry. Enzyme-linked immunosorbent assays were utilized to determine cytokines. Statistical evaluations were performed using non-parametric group comparisons and correlations. A logistic regression model was used to determine predictive values of CD4(+)CD28(null) in the diagnosis of COPD. Populations of CD4(+) T cells lacking surface co-stimulatory CD28 were enlarged significantly in evaluated patients when compared with controls. Natural killer (NK)-like T cell receptors (CD94, 158) and intracellular perforin, granzyme B were increased in CD4(+)CD28(null) cells. Cytokine production after triggering of peripheral blood mononuclear cells (PBMCs) was elevated in patients at early disease stages. Receiver operating characteristic curve plotting revealed that presence of CD4(+)CD28(null) T cells has a diagnostic value. These CD4(+)CD28(null) T cells show increased expression of NK-like T cell receptors (CD94, 158) and intracellular perforin and granzyme B. Furthermore, triggering of PBMCs obtained from patients with mild COPD led to increased interferon-gamma and tumour necrosis factor-alpha production in vitro compared with controls. Our finding of increased CD4(+)CD28(null) T cells in COPD indicates that chronic antigen exposure, e.g. through contents of smoke, leads to loss of CD28 and up-regulation of NK cell receptors expression on T cells in susceptible patients.
Lambers
C
C
Department of Pulmonary Medicine, Medical University of Vienna, Vienna, Austria.
Hacker
S
S
Posch
M
M
Hoetzenecker
K
K
Pollreisz
A
A
Lichtenauer
M
M
Klepetko
W
W
Ankersmit
H Jan
HJ
D000368:Aged; D015415:Biomarkers / Q000032:analysis; D018106:CD28 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology*; D016022:Case-Control Studies; D016922:Cellular Senescence; D016207:Cytokines / Q000032:analysis; D005260:Female; D005434:Flow Cytometry; D053804:Granzymes / Q000032:analysis; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D016015:Logistic Models; D008168:Lung / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D054353:Perforin / Q000032:analysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000503:physiopathology; D012372:ROC Curve; D012907:Smoking / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology
D015415:Biomarkers; D018106:CD28 Antigens; D016207:Cytokines; D054353:Perforin; D053804:Granzymes