Chronic cigarette smoke exposure generates pathogenic T cells capable of driving COPD-like disease in Rag2-/- mice.
BACKGROUND
Pathogenic T cells drive, or sustain, a number of inflammatory diseases. Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with the accumulation of activated T cells. We previously demonstrated that chronic cigarette smoke (CS) exposure causes oligoclonal expansion of lung CD4(+) T cells and CD8(+) T cells in a mouse model of COPD, thus implicating these cells in disease pathogenesis.


OBJECTIVE
To determine whether T cells are pathogenic in a CS-induced mouse model of COPD.


METHODS
We transferred lung CD3(+) T cells from filtered air (FA)- and CS-exposed mice into Rag2(-/-) recipients. Endpoints associated with the COPD phenotype were then measured.


RESULTS
Here, we demonstrate that chronic CS exposure generates pathogenic T cells. Transfer of CD3(+) T cells from the lungs of CS-exposed mice into Rag2(-/-) recipients led to substantial pulmonary changes pathognomonic of COPD. These changes included monocyte/macrophage and neutrophil accumulation, increased expression of cytokines and chemokines, activation of proteases, apoptosis of alveolar epithelial cells, matrix degradation, and airspace enlargement reminiscent of emphysema.


CONCLUSIONS
These data formally demonstrate, for the first time, that chronic CS exposure leads to the generation of pathogenic T cells capable of inducing COPD-like disease in Rag2(-/-) mice. This report provides novel insights into COPD pathogenesis.
Department of Environmental Health, Division of Environmental Genetics and Molecular Toxicology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0056, USA.
Gregory T
GT
Motz
Bryan L
BL
Eppert
Scott C
SC
Wesselkamper
Jennifer L
JL
Flury
Michael T
MT
Borchers
D000818:Animals; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D017252:CD3 Complex / Q000276:immunology; D002403:Cathepsins / Q000378:metabolism; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D007962:Leukocytes / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011650:Pulmonary Alveoli / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
D017252:CD3 Complex; D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D014028:Tobacco Smoke Pollution; D002403:Cathepsins; C028217:cathepsin S; D053508:Matrix Metalloproteinase 12