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Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma

Nature Reviews Immunology volume 8, pages 193–204 (2008)Cite this article

Key Points

  • Asthma is a T helper 2 (TH2)-cell-mediated disorder characterized by airway eosinophilia, goblet-cell hyperplasia and bronchial hyper-reactivity.

  • Dendritic cells (DCs) sample the airway luminal content for the presence of allergens by crossing the airway epithelial-cell barrier.

  • Most clinically relevant allergens can promote allergic sensitization by directly inducing DC activation or by stimulating bronchial epithelial cells.

  • Bronchial epithelial cells induce the activation and TH2-cell polarizing capacity of DCs by producing key cytokines such as thymic stromal lymphopoeitin (TSLP) and granulocyte/macrophage colony-stimulating factor.

  • DCs are important not only for inducing TH2-cell sensitization, but also for maintaining effector TH2-cell responses during ongoing allergic disease.

  • Drugs that selectively target the function of airway DCs could eventually be used for the treatment of asthma.

Abstract

Dendritic cells (DCs) are generally held responsible for initiating and maintaining allergic T helper 2 (TH2)-cell responses to inhaled allergens in asthma. Although the epithelium was initially considered to function solely as a physical barrier, it is now seen as a central player in the TH2-cell sensitization process by influencing the function of DCs. Clinically relevant allergens, as well as known environmental and genetic risk factors for allergy and asthma, often interfere directly or indirectly with the innate immune functions of airway epithelial cells and DCs. A better understanding of these interactions, ascertained from human and animal studies, might lead to better prevention and treatment of asthma.

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Figure 1: A central role for inflammatory TH2 cells in asthma.
Figure 2: Interactions between epithelial cells and dendritic cells in the airways.
Figure 3: TSLP takes centre stage in driving dendritic-cell maturation for TH2-cell responses.
Figure 4: Unifying concept for understanding TH2-cell sensitization.

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Authors and Affiliations

  1. Department of Respiratory Diseases, Laboratory of Immunoregulation and Mucosal Immunology, University Hospital Ghent, Belgium

    Hamida Hammad & Bart N. Lambrecht

  2. Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

    Bart N. Lambrecht

Authors
  1. Hamida Hammad
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Corresponding author

Correspondence to Bart N. Lambrecht.

Supplementary information

Supplementary information S1 (Movie)

Dual photon imaging of a fresh tracheal explant of a transgenic RAG (recombination activating gene)-deficient mouse in which endogenous MHC class II has been replaced by a fusion of the MHC class II protein with GFP (green fluorescent protein). In these mice, dendritic cells (DCs) are the only cells expressing GFP–MHC class II molecules, thereby allowing their identification by imaging techniques without the need for staining. In this image, a green GFP-expressing DC is seen to crawl up to the border of the epithelial-cell layer and to extend its dendrites into the airway lumen. Epithelial cells are stained red using SNARF-1. (AVI 7151 kb)

Glossary

TH2 cells

(T helper 2 cells). A type of T cell that, through the production of interleukin-4 (IL-4), IL-13 and other cytokines, can help B cells to produce IgE and other antibodies and, through the secretion of IL-5, IL-3 and others, can promote increased numbers of eosinophilic granulocytes (eosinophils), basophils and mast cells.

Hyperplasia

An increase in the number of cells in a tissue or organ.

Bronchial hyper-reactivity

The tendency of an asthmatic's immune system to overreact to a variety of nonspecific stimuli. This is measured in a physiology laboratory by changes in airway resistance induced by pharmacological stimuli, such as methacholine or histamine, and expressed as the concentration of a stimulus that induces a 20% drop in lung function (that is, the PC20 value).

Atopic

The propensity of an individual to develop allergic diseases, such as asthma, atopic dermatitis, food allergy or hay fever. It is defined operationally by elevations in serum levels of IgE reactive with allergens or by skin-test reactivity to allergens.

Transepithelial electrical resistance

An assay in which epithelial-cell monolayers are grown on a permeable membrane and exposed to a high concentration of electrolytes on the basolateral side, and a low concentration on the apical side, thereby generating an electrochemical gradient. The electrical resistance between basolateral and apical side is a measure of the permeability of the epithelium.

Tight junction

A belt-like region of adhesion between adjacent epithelial or endothelial cells that regulates paracellular flux. Tight-junction proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zonula occludens proteins.

Adjuvant

An agent mixed with an antigen that increases the immune response to that antigen after immunization.

Osteopontin

An extracellular-matrix protein that supports adhesion and migration of inflammatory cells. It has recently been recognized as an immunoregulatory T-helper-1-type cytokine.

Inflammasome

A molecular complex of several proteins that upon assembly cleaves pro-IL-1, thereby producing active IL-1.

β-catenin pathway

This multitalented protein functions both as a transcriptional activator and as a membrane-cytoskeleton linker protein by binding to E-cadherin. Upon detachment from E-cadherin it can relocate to the nucleus.

Eicosanoids

Fatty-acid derivatives, primarily derived from arachidonic-acid precursors, that have a wide variety of biological activities. There are four main classes of eicosanoid — the prostaglandins, prostacyclins, thromboxanes and leukotrienes — derived from the activities of cyclooxygenases and lipoxygenases on membrane-associated fatty-acid precursors.

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Hammad, H., Lambrecht, B. Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat Rev Immunol 8, 193–204 (2008). https://doi.org/10.1038/nri2275

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