Lung Myeloid Dendritic Cells Coordinately Induce T _H 1 and T _H 17 Responses in Human Emphysema

Abstract

Exposure to tobacco smoke activates innate and adaptive immune responses that in long-term smokers have been linked to diseases of the lungs, cardiovascular system, joints, and other organs. The destruction of lung tissue that underlies smoking-induced emphysema has been associated with T helper 1 cells that recognize the matrix protein elastin. Factors that result in the development of such autoreactive T cells in smokers remain unknown but are crucial for further understanding the pathogenesis of systemic inflammatory diseases in smokers. Here, we show that lung myeloid dendritic cells were sufficient to induce T helper 1 and T helper 17 responses in CD4 T cells. T helper 1 and 17 cells are invariably present in lungs from patients with emphysema but not in lungs from normal individuals. Interleukin-17A, a canonical T helper 17 cytokine, enhanced secretion of CCL20, a chemoattractant for dendritic cells, and matrix metalloproteinase 12, a potent elastolytic proteinase, from lung macrophages. Thus, although diverse lung factors potentially contribute to T helper effector differentiation in vivo, lung myeloid dendritic cells direct the generation of pathogenic T cells and support a feedback mechanism that sustains both inflammatory cell recruitment and lung destruction. This mechanism may underlie disease in other elastin-rich organs and tissues.

Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8–mediated activation of TGF-β

“…Specifically, lung DCs migrate utilizing chemokine/receptor pairs CCL2/CCR2, CCL7/CCR2, CCL5/CCR5, and CCL20/CCR6 (22)(23)(24). CCL2 and CCL20 expression is increased in human COPD and asthma lung samples (20,(25)(26)(27)(28). Furthermore, Ccr6 -/-mice are protected from cigarette smoke-induced airway wall remodeling, and both Ccr2 -/-and Ccr6 -/-mice are protected from allergic pulmonary inflammation (29)(30)(31).…”

“…The Ad-IL-1β model has many physiologically relevant features, since it recapitulates most of the morphologic and immunologic characteristics of airway remodeling in COPD in humans. Specifically, there are increases in airway wall fibrosis and airway wall inflammation; and a COPD-like innate and adaptive immune response, with increased neutrophils, mDCs, and Th17 and Th1 cells and increased production of IL-17, CCL2 and CCL20 (20).…”

“…Conversely, in asthma, a Th2-type response is primed, characterized by production of IL-4, IL-5, IL-9, and IL-13 (5,(16)(17)(18)(19)(20).…”

Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema

“…Recent studies have, however, elucidated a role for acquired immunity in the development of emphysema in humans and mice, including the importance of Th1 and Th17 cells (11)(12)(13)(14)(15)(16). We recently cloned elastin-specific T cells from the peripheral blood of smokers with emphysema and showed that this autoimmune phenomenon predicts clinically relevant outcomes (17).…”

Soluble common gamma chain exacerbates COPD progress through the regulation of inflammatory T cell response in mice

“…1,31,32 Previous studies have reported that the levels of Th1-and Th17-related cytokines in lung tissues of COPD patients are increased and play a pivotal role in the progression of COPD. 33,34 Since sγc was identified as regulators of Th1 and Th17 differentiation, 22 it is logical that sγc may closely be related to the immunopathogenesis of COPD. Here, we assessed the pattern of sγc expression on COPD development and found that the expression of sγc was dramatically reduced in a CSE-induced COPD mouse model.…”