Lung Dendritic Cells: Shaping Immune Responses throughout Chronic Obstructive Pulmonary Disease Progression

Abstract

Hallmarks of chronic obstructive pulmonary disease (COPD) include innate inflammation and remodeling of small airways, which begin in early disease, and the development of lung lymphoid follicles (LLF), indicative of adaptive immunity, in more spirometrically severe stages. Common to these processes in all stages is orchestration by dendritic cells (DCs). Recently improved understanding of the analogous lung DC subsets in humans and mice has allowed for better integration and interpretation of the experimental and clinical pathological literature. In this review, we summarize the evidence from human and animal studies to place lung DCs into the context of COPD pathogenesis. We highlight recent studies that demonstrate a potential role for DCs in airway remodeling and that call into question the long-standing belief that intraepithelial DCs actively sample airway lumens. We discuss how DCs drive LLF formation directly and indirectly and also examine the ability of DCs within LLF to instruct downstream effector functions of natural killer cells, CD4+ T cells, and regulatory T cells. Greater awareness of the multifaceted functions of DCs will be essential in the quest to identify new therapeutic modalities to treat COPD.

Keywords: chronic obstructive pulmonary disease; dendritic cells; lung.

Figures

Figure 1.

Recruitment and role of DCs in small airways. (A) Beginning in the small airways, CCR6+ DCs are recruited to the site of inflammation via CCL20, expressed by epithelial cells or fibroblasts. (B) Activated DCs secrete IL-6, which drives activated B cells to turn into IgA-producing plasma cells. (C) In healthy lung tissue, pIgR is necessary to transport dimeric IgA across epithelial cells to the airway lumen; there, it is cleaved to generate sIgA, which prevents binding of microbes and neutralizes their toxins. In chronic obstructive pulmonary disease, decreased pIgR leads to decreased sIgA and a corresponding increase in commensal bacteria localized within the epithelium. Bacterial “invasion” could trigger DCs to initiate additional immune responses. CCL, C-C motif chemokine ligand; CCR, C-C motif chemokine receptor; DC, dendritic cell; DLN, draining lymph node; pIgR, polymeric Ig receptor; sIgA, secretory IgA.

Figure 2.

Lung DCs in LLF. Lung DCs can contribute to the formation of LLF. In addition to draining lymph nodes, LLF provide a microenvironment where DCs interact with other cells. (A) Antigen uptake may also be occurring in LLF, where many DCs, including CD103+/Langerin+ DCs, directly interface with the alveolar spaces (52). (B) CD103+ DCs drive Th1 and Th17 responses in chronic obstructive pulmonary disease, whereas IL-17 production can initiate development of new LLF. (C) Signals from DCs could prime CD57+ NK cells to become cytotoxic and kill epithelial cells. CD, cluster of differentiation; fDC, follicular DCs; LLF, lung lymphoid follicles; NK, natural killer; Th, T helper cell.