Persistence of Lung CD8 T Cell Oligoclonal Expansions upon Smoking Cessation in a Mouse Model of Cigarette Smoke-Induced Emphysema

Abstract

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 V␤ 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 V␤ repertoire analyses revealed oligoclonal expansions predominantly occurred in lung CD8 T cells, with preferential usage of V␤7, V␤9, V␤13, and V␤14. Using nucleotide sequence analysis based on J␤ analyses, we demonstrate selection of CDR3 amino acid motifs, which strongly suggests Ag-driven oligoclonal T cell expansion. Analysis of the lung TCR V␤ 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.

Chronic Obstructive Pulmonary Disease: Evidence for an Autoimmune Component

“…Oligoclonal CD8 + T cell infiltrates are present in both the lungs of COPD patients and also in mice chronically exposed to cigarette smoke, where they persist even after a sustained period of smoking cessation (32,33). Furthermore, a number of groups have demonstrated that CD8 + T cell infiltration is positively correlated with airflow limitation and disease progression (31,34).…”

Chronic Cigarette Smoke Exposure Primes NK Cell Activation in a Mouse Model of Chronic Obstructive Pulmonary Disease

“…Bitransgenic Ccsp-rtta 3 (tetO) 7 -CMV-Raet1a (FVB/NJ background, henceforth referred to as Raet1a-tg mice) mice were generated as described (6,25). Raet1a-tg mice conditionally express Raet1a on the alveolar and airway epithelium in a doxycycline (DOX)-inducible manner (6,25).…”

“…Lungs were perfused with 6 ml 13 PBS containing 0.6 mM EDTA. Lungs were withdrawn aseptically from the chest cavity, and leukocytes were isolated in a manner previously described (7). Spleen leukocytes were prepared by gently pressing spleens through a 100-mm cell strainer in 5 ml RPMI 1640.…”

“…Attention has traditionally been centered on the roles of macrophages and neutrophils in disease development (4). However, lymphocytes have received increased attention, and reports from our laboratory have provided insight into functions of T cells and NK cells in COPD (6)(7)(8).…”

Second hand smoke and COPD: lessons from animal studies

“…Within 1 week of smoking cessation, there is a partial normalization of MMP-2 and MMP-9 levels in BAL fluid (Seagrave et al, 2004), though lymphocyte abnormalities including CD8 T cell oligoclonal expansions persist (Seagrave et al, 2004;Motz et al, 2008). It is likely that the combination of altered inflammatory response and cytokine profiles are responsible for the variations between strains in structural and functional measures of emphysema as well as for the reparative response seen upon smoking cessation.…”