Review www.thelancet.com Vol 376 September 4, 2010 835 Lancet 2010; 376: 835–43 Laboratory of Immunoregulation and Mucosal Immunology, Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium (B N Lambrecht MD, H Hammad PhD) Correspondence to: Dr Bart N Lambrecht, Laboratory of Immunoregulation and Mucosal Immunology, Department of Pulmonary Medicine, University Hospital Ghent, De Pintelaan 185, B9000 Gent, Belgium bart.lambrecht@ugent.be The role of dendritic and epithelial cells as master regulators of allergic airway inflammation Bart N Lambrecht, Hamida Hammad 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. 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 CD11c hi conventional dendritic cells (cDCs) and CD11c dim plasmacytoid dendritic cells (pDCs); additional divisions can be made on the basis of CD11b marker expression, typically expressed on myeloid lineage cells. When studying subsets of dendritic cells, it is important to separate large conducting airways from lung parenchyma 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.