Chronic Cigarette Smoke Exposure Generates Pathogenic T Cells Capable of Driving COPD-like Disease in Rag2^−/− Mice

Abstract

Rationale: 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 1 T cells and CD8 1 T cells in a mouse model of COPD, thus implicating these cells in disease pathogenesis. Objectives: To determine whether T cells are pathogenic in a CSinduced mouse model of COPD. Methods: We transferred lung CD3 1 T cells from filtered air (FA)-and CS-exposed mice into Rag2 2/2 recipients. Endpoints associated with the COPD phenotype were then measured. Measurements and Main Results: Here, we demonstrate that chronic CS exposure generates pathogenic T cells. Transfer of CD3 1 T cells from the lungs of CS-exposed mice into Rag2 2/2 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 2/2 mice. This report provides novel insights into COPD pathogenesis.

Differential switching to IgG and IgA in active smoking COPD patients and healthy controls

“…In addition to B-cells, the presence of oligoclonal CD4-positive T-cells has been demonstrated in the lung tissue of severe COPD patients [13] as well as an antigen-specific T-helper type 1 response to lung elastin [14]. Consistent with this, MOTZ et al [15] recently demonstrated that chronic cigarette smoke exposure can generate T-cells in mice that are capable of inducing a COPD-like pathology upon transfer to naïve recipients lacking functional T-and B-cells. To our knowledge, the study by MOTZ et al [15] is the first functional study demonstrating smokeinduced autoreactivity with COPD-like pathology in mice.…”

“…Consistent with this, MOTZ et al [15] recently demonstrated that chronic cigarette smoke exposure can generate T-cells in mice that are capable of inducing a COPD-like pathology upon transfer to naïve recipients lacking functional T-and B-cells. To our knowledge, the study by MOTZ et al [15] is the first functional study demonstrating smokeinduced autoreactivity with COPD-like pathology in mice.…”

Experimental Therapeutics of Nrf2 as a Target for Prevention of Bacterial Exacerbations in COPD

“…In both airways and lung parenchyma, the number of CD4 1 and CD8 1 cells is elevated in COPD and correlates directly with decrease in lung function (1). Unequivocally, results from mouse models of chronic exposure to cigarette smoke have shown that pathogenic T cells capable of driving alveolar destruction are induced in the lungs (4). Transfer of CD3 1 T cells from the lungs of mice exposed to cigarette smoke for 6 months into normal Rag2 2/2 mice, which are deficient in T and B cells, induced pulmonary inflammation and emphysema (4).…”

“…Unequivocally, results from mouse models of chronic exposure to cigarette smoke have shown that pathogenic T cells capable of driving alveolar destruction are induced in the lungs (4). Transfer of CD3 1 T cells from the lungs of mice exposed to cigarette smoke for 6 months into normal Rag2 2/2 mice, which are deficient in T and B cells, induced pulmonary inflammation and emphysema (4). The component that activates adaptive immune responses is still an area of intense investigation, and it is thought that DAMPs released by damaged tissue or apoptotic or necrotic cells may function as antigens and be processed by dendritic cells (DCs) and elicit adaptive immune responses.…”

Lung Diseases - Selected State of the Art Reviews

“…The presence of neutrophils, BALT collections, autoantibodies in the lungs, and also autoreactive T cells in the periphery, indicate CD4 + T cell involvement in the pathogenesis of COPD (Curtis, Freeman, and Hogg 2007;Feghali-Bostwick et al 2008;Hogg et al 2004;Vanaudenaerde et al 2011). A potential role for adaptive immune responses in COPD has also been suggested in studies that show expansion of lung T and B cells with oligoclonality in patients with COPD and in murine emphysema models (Motz et al 2010;Sullivan et al 2005). To date, there are only few studies examining the expression of IL-17A and IL-17F in COPD.…”