Dendritic cells in lung immunopathology

Abstract

Dendritic cells (DCs) lie at the heart of the innate immune system, specialised at recognising danger signals in many forms including foreign material, infection or tissue damage and initiating powerful adaptive immune and inflammatory responses. In barrier sites such as the lung, the instrumental role that DCs play at the interface between the environment and the host places them in a pivotal position in determining the severity of inflammatory disease. The past few years has seen a significant increase in our fundamental understanding of the subsets of DCs involved in pulmonary immunity, as well as the mechanisms by which they are activated and which they may use to coordinate downstream inflammation and pathology. In this review, we will summarise current understanding of the multi-faceted role that DCs play in the induction, maintenance and regulation of lung immunopathology, with an emphasis on allergic pulmonary disease.

Keywords: Allergies; Asthma; Dendritic cells; Lung; Th17; Th2.

Fig. 1

Key players in type 2/type 17 pulmonary inflammation and immunopathology. a The lung is continually exposed to a variety of signals that can trigger immune responses. In a healthy lung, exposure of epithelial cells (ECs) to danger signals triggers damage responses and the release of tissue factor cytokines such as TSLP IL-25 IL-33 and TGFβ [39, 50, 51, 173]. Simultaneously, antigens/allergens from the airspaces directly activate dendritic cells (DCs) located in the lung mucosa under the epithelial barrier [59, 86, 126]. The tissue factors released by the epithelium can not only influence the DCs directly but also indirectly via other innate cells such as innate lymphoid cells (ILCs) to alter DC activation or migration and promote allergic inflammation [52, 53]. Activated DCs can secrete a variety of proinflammatory mediators such as IL-6 and TNFα that may influence other innate cells in the lung such as intersitial macrophages (MΦs). Simultaneously, these DCs can also secrete regulatory cytokines such as TGF-β, promoting the generation of inducible regulatory T cells (iTregs) [152]. DCs then migrate to the draining lymph node (LN) via CCR7 to prime and polarise Th2, Th17 and iTreg cells, a process that may be assisted by cytokine production by accessory cells such as ILCs. The mechanism(s) by which this is achieved, and how these responses are balanced, is not yet clear. b During chronic exposure to inflammatory signals from antigens/allergens and/or innate cells, DCs release chemokines such as CCL17 and CCL22 to recruit effector Th2 and Th17 cells to the lungs, promoting the type 2/type 17 allergic inflammatory environment. It is unknown the extent to which DCs collaborate with other innate cells such as ILCs in the activation of recruited T cell populations, or innate effector cells such as granulocytes (MC; mast cells, Bas; basophils, Eos; eosinophils) and MΦs, to maintain chronic type 2 or type 17 inflammation in the lung. In type 2 settings, this process is also influenced by B cells releasing IgE that can bind to FcR-expressing innate cells. In contrast, type 17 responses promote neutrophil (Neut) infiltration, which may also impact activation and function of innate effector populations such as MΦs [174]. In both type 2 and type 17 settings, soluble mediators from innate and adaptive effectors can then mediate disease features such as goblet cell (GC) hyperplasia and smooth muscle (SM) contraction [–65, 78]. Thus, DCs play a central role in promoting or regulating chronic pulmonary disease (1) through their central ability to initiate and direct primary responses and (2) through influencing effector cell recruitment and activation during ongoing inflammation. They achieve this through cross-talk with a diverse range of innate and adaptive effector populations, via production of soluble mediators and/or direct cell contact. Defining the specific DC subsets involved and the precise mechanisms they employ to communicate with these diverse effector cells, and how this changes over the course of chronic inflammatory disease and in different disease settings, will reveal new avenues for therapeutic intervention