Airway Macrophage and Dendritic Cell Subsets in the Resting Human Lung

Abstract

Dendritic cells (DCs) and macrophages (MΦs) are antigen-presenting phagocytic cells found in many peripheral tissues of the human body, including the blood, lymph nodes, skin, and lung. They are vital to maintaining steady-state respiration in the human lung based on their ability to clear airways while also directing tolerogenic or inflammatory responses based on specific stimuli. Over the past three decades, studies have determined that there are multiple subsets of these two general cell types that exist in the airways and interstitium. Identifying these numerous subsets has proven challenging, especially with the unique microenvironments present in the lung. Cells found in the vasculature are not the same subsets found in the skin or the lung, as demonstrated by surface marker expression. By transcriptional profiling, these subsets show similarities but also major differences. Primary human lung cells and/ or tissues are difficult to acquire, particularly in a healthy condition. Additionally, surface marker screening and transcriptional profiling are continually identifying new DC and MΦ subsets. While the overall field is moving forward, we emphasize that more attention needs to focus on replicating the steady-state microenvironment of the lung to reveal the physiological functions of these subsets.

FIG. 1:

Human lung anatomy. Inhaled air travels down the trachea, enters the lungs, and follows a network of branching bronchi and bronchioles until it reaches the terminal bronchioles and the alveoli. An ascending network of lymphatic vessels (right side) carries lymph, particulates, and immune cells from the interstitial spaces to the hilar and eventually the mediastinal lymph nodes. Inset: The alveoli are grape-like structures responsible for exchange of oxygen and carbon dioxide.

FIG. 2:

Human alveolar structure and cellular composition. At the alveolar level, oxygen diffuses into and carbon dioxide diffuses out of blood flowing through pulmonary capillaries. Inset: A wide variety of cell types are found in and around alveoli. Type I AECs make up the majority of the surface area involved in respiration. DCs are found embedded within the alveolar epithelium and just below it in the submucosa, from where they extend processes into the alveolar space to sample antigens. Immune cells transit between alveoli via pores of Kohn. Together, subsets of macrophages, dendritic cells, and tissue monocytes keep the airways clear of obstruction and direct interactions with cells of the adaptive immune system.

FIG. 3:

Summary diagram of stepwise human lung MΦs and monocyte subset identification, including markers and microenvironment. MHC, major histocompatibility complex; APC, antigen-presenting cell; AF, autofluorescence; FSC, forward scatter; SSC, side scatter.