T cell senescence and contraction of T cell repertoire diversity in patients with chronic obstructive pulmonary disease

Clin Exp Immunol. 2009 Mar;155(3):466-75. doi: 10.1111/j.1365-2249.2008.03835.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers / analysis
  • CD28 Antigens
  • CD4-Positive T-Lymphocytes / pathology*
  • Case-Control Studies
  • Cellular Senescence
  • Cytokines / analysis
  • Female
  • Flow Cytometry
  • Granzymes / analysis
  • Humans
  • Killer Cells, Natural / immunology
  • Logistic Models
  • Lung / physiopathology
  • Male
  • Middle Aged
  • Perforin / analysis
  • Pulmonary Disease, Chronic Obstructive / immunology*
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • ROC Curve
  • Smoking / immunology
  • T-Lymphocyte Subsets / immunology


  • Biomarkers
  • CD28 Antigens
  • Cytokines
  • Perforin
  • Granzymes