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* Department of Environmental Health, Division of Environmental Genetics and Molecular Toxicology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267;
Department of Environmental Health, Center for Genome Information, University of Cincinnati, College of Medicine, Cincinnati, OH 45267;
Veterans Affairs Medical Center, Research Service, Cincinnati, OH 45220;
Department of Internal Medicine, Division of Infectious Diseases, University of Cincinnati, College of Medicine, Cincinnati, OH 45267; and
¶ Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, College of Medicine, Cincinnati, OH 45267
The role of adaptive immunity in the development or progression of chronic obstructive pulmonary disease (COPD) remains undefined. Recently, the presence of autoantibodies and autoreactive T cells has been demonstrated in COPD patients. In addition, oligoclonal expansions of lung T cells have been observed in COPD patients, but the overlapping incidence of infections, tumors, and cigarette smoke exposure obscures the antigenic stimulus. We analyzed the TCR Vβ repertoire of CD4 and CD8 T cells purified from the lungs and spleens of mice chronically exposed to cigarette smoke. In a mouse model of COPD, we demonstrate that chronic cigarette smoke exposure causes oligoclonal expansions of T cells isolated from the lungs, but not spleens. TCR Vβ repertoire analyses revealed oligoclonal expansions predominantly occurred in lung CD8 T cells, with preferential usage of Vβ7, Vβ9, Vβ13, and Vβ14. Using nucleotide sequence analysis based on Jβ analyses, we demonstrate selection of CDR3 amino acid motifs, which strongly suggests Ag-driven oligoclonal T cell expansion. Analysis of the lung TCR Vβ repertoire of mice with cigarette smoke-induced emphysema, which had undergone smoking cessation for 6 mo, revealed that oligoclonal expansions persisted. This study formally demonstrates that chronic cigarette smoke exposure, alone, causes a persistent adaptive T cell immune response. These findings have important implications for therapeutic approaches in the treatment of COPD, and provide insight into potential mechanisms involved in disease pathogenesis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Environmental Health Sciences (Grant ES015036 to M.T.B., Training Grant ES07250 to G.T.M.), and the Center for Environmental Genetics Grant P30-ES06096.
2 Address correspondence and reprint requests to Dr. Michael T. Borchers, Department of Environmental Health, P.O. Box 670056, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0056. E-mail address: michael.borchers{at}uc.edu
3 Abbreviation used in this paper: COPD, chronic obstructive pulmonary disease.
4 The online version of this article contains supplementary material.
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