T cells and smoke-induced airway inflammation

Abstract: Chronic obstructive pulmonary disease (COPD) is an inflammatory disease primarily caused by longterm cigarette smoking. The disease is characterized by both tissue remodelling and an accumulation of inflammatory cells including macrophages, neutrophils and T cells, in the lung. However, the mechanisms through which T cells contribute to disease progression and tissue remodelling remain unclear. In the present work we sought to clarify the role of T cells in smoke-induced inflammation. Specifically, we studied how T cells interact with fibroblasts in an in vitro model for tissue remodelling. We also elucidated how environmental factors, such as smoking and hypoxia, present in the lungs of COPD patients, affect the T cell secretion of cytokines and vascular endothelial growth factor (VEGF). Further, we studied the neurotrophins in the lungs of neversmokers, smokers and COPD patients. Finally, we characterised T cells in blood and bronchoalveolar lavage (BAL) fluid from smokers, never-smokers and patients with COPD in order to better understand the role of T cells in the pathophysiology of the disease. Activated peripheral T cells stimulated fibroblasts to cause collagen gel contraction and collagendegradation in vitro. CD4+ T cells stimulated more than CD8+ T cells did, and MMP-9 activity was increased in CD4+ T cell stimulated conditions. Also, CD4+ T cells secreted more IL-6 and TNF than CD8+ T cells did, and IFN-gamma was abundantly secreted by both, indicating a role for these cytokines in the remodelling process. Hypoxia significantly stimulated peripheral T cells to secrete VEGF, whereas the cytokines IL-4, IL-6, IL-10, IL-13, IFN-gamma and TNF were unaffected. In contrast, cigarette smoke inhibited cytokine secretion whereas VEGF secretion was unaltered. Moreover, adding VEGF reversed the smokeinduced reduction of IL-13 and IFN-gamma secretion. T cells from COPD patients secreted more VEGF than did T cells from controls. The neurotrophins NGF and NT-3 were decreased in airway samples from both smokers and patients with COPD compared to those from non-smokers. Lung fibroblasts exposed to cigarette smoke in vitro had a lower gene expression and protein secretion of both NGF and NT-3 than did fibroblasts not exposed to smoke. The frequency of CD8+CD103+ T cells was higher in the airways of smokers and COPD patients than in the airways of neversmokers. However, within this population of T cells, a subset (CD27+ CD69-HLA-DR-) was decreased in smokers and in COPD patients. Further, CD4+FoxP3+ regulatory T cells (Tregs) were increased in the airways of smokers than in those of neversmokers. We demonstrate that CD4+ T cells can interact with fibroblasts, thereby stimulating tissue degradation a potential mechanism for the development of pulmonary emphysema. We further show that environmental factors such as hypoxia and cigarette smoke affect the T cell response. Neurotrophin levels were lower in the lungs of smokers and COPD patients, which may potentially hamper repair mechanisms by structural cells. We also demonstrate that CD8+ T cells in the lungs of smokers and COPD patients are not only increased but also have altered phenotypes compared to those of neversmokers. Based on data presented in this thesis, we conclude that smoke-induced inflammation has a significant effect both on T cell phenotype and on the ability of T cells, via cytokines and other mediators, to interact with other cells present in the lung. Our findings shed light on the role of T cells in smoke-induced inflammation and highlight their role in the development of COPD.