Innate cells and T helper 2 cell immunity in airway inflammation

Abstract

Activated mast cells, eosinophils, and basophils infiltrate the airways of asthmatics as a result of an overexuberant T helper 2 (Th2) cell immune response that drives the production of IgE, primes mast cells and basophils, and promotes tissue eosinophilia and mast cell hyperplasia. Recent evidence demonstrates that these innate effectors can be activated outside of this classical Th2 cell paradigm and that they have additional roles in promoting the development of innate and adaptive pulmonary inflammation. There is also an appreciation for the role of airway epithelial cells in orchestrating allergic pulmonary inflammation. Emerging data from basic research highlight the involvement of many unique pathways in the inflammation triggered by complex native allergens and microbes at the airway mucosal surface. Here, we review the role of effector cells and airway epithelial cells in augmenting and, at times, bypassing traditional Th2 cell-mediated allergic inflammation.

Figure 1. Innate Cells and Their Mediators Modulate the Development of Th2 Immune Responses

(Upper left) Activated eosinophils (Eos) release EDN which acts at DC TLR2 to mature DCs, to generate IL-6, IL-8, IL-12p70, and TNF-α, and to enhance the production of antigen-specific Th2 cytokines and serum IgG1. MC-derived TNF-α facilitates DC migration to the LN. MCs facilitate DC Ag presentation by taking up Ag and either releasing it in exosomes or apoptosing for subsequent DC phagocytosis and activation. Activated MCs and Basophils (B) produce TSLP which upregulates OX40L on DCs for the subsequent generation of Th2 immunity. (Lower left) In the lymph node, basophils direct Th2 development with the generation of IL-4 and TSLP. (Lower right) Basophils can present soluble antigen to direct Th2 development, which is augmented by the presence of antigen-specific IgE and critical to the generation of Th2 immunity during helminth infection. (Upper right) IL-33, IL-25, and TSLP potentiate the proliferation of committed Th2 cells as well as their cytokine production.

Figure 2. Airway Inflammation, Smooth Muscle Constriction, and Airway Remodeling Generated by Innate Effectors

(Left) PAMPs associated with microbes or allergens such as peptidoglycan, zymosan, chitin, and mannose-rich ligands from dust mites and fungi, directly elicit arachidonic acid metabolism and inflammatory cytokines from tissue-resident effector cells such as DCs, MCs, and macrophages (MΦ). Chitin-induced eosinophilic inflammation is independent of STAT6 and RAG2. (Center) Allergens stimulate epithelial cell generation of IL-33, TSLP, and IL-25. While TSLP induces MC generation of Th2 cytokines, IL-33 acts more broadly on MCs, eosinophils (Eo), and basophils (B) to elicit Th2 cytokines. IL-33-induced goblet cell metaplasia and AHR is independent of RAG2. IL-25 induces IL-4, IL-5, and IL-13 production from a NBNT cell population, and stimulates i NKTs to generate IL-13 and promote AHR and airway remodeling. IL-25 can induce AHR in Il4^−/−Il5^−/−Il9^−/−Il13^−/− mice. (Right) dsDNA or viral infection induces epithelial cells to produce TSLP which activates MCs to generate Th2 cytokines. i NKTs, activated by viral infection, generate IL-13 and activate IL-13-producing macrophages, in the absence of CD4⁺ cells, to promote AHR and remodeling.