Elsevier

The Lancet

Volume 376, Issue 9743, 4–10 September 2010, Pages 835-843
The Lancet

Review
The role of dendritic and epithelial cells as master regulators of allergic airway inflammation

https://doi.org/10.1016/S0140-6736(10)61226-3Get rights and content

Summary

Lung dendritic cells bridge innate and adaptive immunity, integrating a variety of stimuli from allergens, microbial colonisation, environmental pollution, and innate immune cells into a signal for T lymphocytes of the adaptive immune system. Dendritic cells have a pivotal role in the activation of T helper (Th) 2 cells and allergic inflammation. Lung dendritic cells can also prevent harmful immune responses to innocuous inhaled antigens via induction of regulatory T cells or Th1 cells. In our Review, we discuss how understanding the biology of dendritic cells is crucial for understanding the interaction between allergens, the environment, and genetics, and focus on how dendritic cells conspire with airway epithelial cells and innate pro-Th2 cells to cause allergic sensitisation and asthma.

Introduction

When inhaled antigens are not filtered by the upper airways, they can deposit on the epithelial linings of the trachea and bronchi or even the deep alveolar compartment, where, if harmless, they are cleared by mucociliary transport or phagocytosed by alveolar macrophages that neutralise antigens, even when they are inherently pathogenic.1 Inhaled pathogens trigger pattern recognition receptors of the innate immune system such as Toll-like receptors (TLRs) on epithelial cells and macrophages that can lead to chemokine production and recruitment of additional neutrophilic leucocytes of the innate immune system. This acute neutrophilic inflammation kills inhaled pathogens, thus limiting local infection and their systemic spread. In ideal cases, after such an acute event, long-lived memory in the immune system is induced, made up of T and B lymphocytes of the adaptive immune system that provide cytokines to help innate immunity and provide a source of long-lived neutralising antibodies, preventing re-infection. To bridge innate and adaptive immunity, there is a specialised population of innate immune antigen presenting cells, dendritic cells, that express all the receptors of the innate immune system and at the same time have the potential to take up antigen, process it into small peptides, and present it in the cleft of major histocompatibility complex (MHC) I and MHCII molecules to be recognised by T cell receptors.2 Dendritic cells line the tissues of the body exposed to the exterior environment such as the skin and the epithelia of the lung and gut, where they patrol the tissues for incoming antigens (figure 1). When an antigen is encountered, the simultaneous triggering of pattern recognition receptors on the surface or within the internalisation vacuoles (endosomes) of dendritic cells leads to their migration to the T-cell area of the draining regional lymph nodes.3 This journey, which takes a few hours, is accompanied by substantial alterations in the expression of adhesion molecules and co-stimulatory molecules for naive T cells (a process called maturation, to distinguish from the immature, antigen-capturing mode in the peripheral tissues), and by the processing of the antigen.4 In the T-cell area, mature dendritic cells arrest and select the rare antigen-specific T lymphocytes and form an immunological synapse for 12–24 h, during which they communicate the nature of the inciting antigen to the T cell, thus inducing an optimum type of T-helper response (figure 2).5 Some T-helper (Th) cells—T follicular helper cells—are transported to the B cell follicle to help immunoglobulin class switching, and others are transported to the site of infection to help innate immune cells to kill pathogens. Th1 cells help macrophages to kill intracellular pathogens, whereas Th17 cells help to fight against extracellular bacteria, fungi, and other organisms by further inducing neutrophil recruitment and immunoglobulin class switching. Thus, by simultaneously recognising foreign antigens and communicating with T lymphocytes, dendritic cells bridge innate and adaptive immunity.

Section snippets

Heterogeneity of dendritic cells of the lung

It is still unknown if all the functions of dendritic cells are done by a single type of cell or if there are many subsets that do these tasks simultaneously or sequentially. In the mouse lung for example, five distinct subsets have been described, characterised by expression of a combination of cell-surface markers as well as anatomical location. These subsets of dendritic cells can be grossly divided into CD11chi conventional dendritic cells (cDCs) and CD11cdim plasmacytoid dendritic cells

Antigen uptake and migration

Intraepithelial dendritic cells are situated in the basolateral layer of the airway epithelium, only separated from the inhaled air by the epithelium tight-junction barrier. In airways, dendritic cells extend their processes between epithelial cells into the airway lumen.13 By forming tight junctions with neighbouring epithelial cells, dendritic cells sample the airway lumen without disturbing the function of the epithelial barrier, a model also proposed in the skin and gut.14, 15 It is clear

Th2 responses and allergic sensitisation

In the general theory of immune functioning, Th2 cells are crucial for the clearance of parasites, such as helminths, via expansion and activation of innate immune system effector cells like eosinophils and basophils, whereas Th1 cells control macrophage activation and Th17 cells are involved in antifungal immunity. Although the signals needed to drive Th1 and Th17 cell differentiation by dendritic cells are now well characterised (figure 2), the mechanisms leading to Th2 cell differentiation

Allergen recognition by dendritic cells

Allergens that cause allergic diseases are very diverse, yet—like helminth-derived secreted products—they are often proteases that also contain trace amounts of bacterial contaminants. One example is the house dust mite, which contains several cysteine protease allergens (Der p 1, Der p 9) and is also contaminated by trace amounts of endotoxin and fungal products derived from the microbial flora of the mite's gastrointestinal tract.39 Unsurprisingly, development of Th2-mediated immunity to

Allergic sensitisation

Allergic sensitisation is a multifactorial process in which exposure to allergens; environmental risk factors, such as maternal cigarette smoking, diet, hygiene, and viral respiratory infection history; and genetics, have a predominant role, particularly in the vulnerable period of early life during which most sensitisations happen. Although complex at first, we propose that many of these contributing factors in some way interfere with communication between epithelial cells and dendritic cells

Secondary allergen challenge

Dendritic cells are not only predominant in understanding allergic sensitisation, they are also crucial during the Th2 effector phase of asthma at times of repeated allergen challenge (figure 1).77 Not only are the number and activation state of these cells enhanced, but also their conditional depletion by genetic strategies in CD11c-diphtheria toxin receptor transgenic mice led to a complete resolution of airway inflammation and salient features of asthma, including bronchial hyper-reactivity.

Dendritic cells as therapeutic targets

Obviously, targeting the function of lung dendritic cells with inhaled compounds is the holy grail of inflammation research, but in our view, it will be hard to find compounds that do not simultaneously raise susceptibility to respiratory infections.7 Strikingly however, inhaled corticosteroids, the mainstay of asthma therapy substantially reduce numbers of dendritic cells in the lungs of asthmatic people, probably contributing to their mechanism of action, without causing severe

Search strategy and selection criteria

Primary published work used for compiling this Review was searched with a Pubmed search strategy for “asthma” and “pathogenesis”; “dendritic cells” and “lung”; and “antigen presenting cells” and “asthma”. We have primarily cited references from 2009 to 2010, and for older data, or for more technical articles where a specific experimental procedure is used we have referred to well cited review articles or methods papers.

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