Innate immunity provides the first line of response to invading pathogens and a variety of environmental insults. Recent studies identified novel subsets of innate lymphoid cells that are capable of mediating immune responses in mucosal organs. Here we describe a subset of lymphoid cells that is involved in innate type-2 immunity in the lungs. Airway exposure of naïve BALB/c or C57BL mice to IL-33 results in a rapid (< 12 h) production of IL-5 and IL-13 and marked airway eosinophilia independently of adaptive immunity. In the lungs of non-sensitized naïve mice, IL-33-responsive cells were identified that have a lymphoid morphology, lack lineage markers, highly express CD25, CD44, Thy1.2, ICOS, Sca-1 and IL-7Rα (i.e. Lin−CD25+CD44hi lymphoid cells), and require IL-7Rα for their development. Airway exposure of naïve mice to a clinically relevant ubiquitous fungal allergen, Alternaria alternata, increases bronchoalveolar lavage levels of IL-33, followed by IL-5 and IL-13 production and airway eosinophilia without T or B cells. This innate type-2 response to the allergen is nearly abolished in mice deficient in IL-33 receptor (i.e. ST2), and the Lin−CD25+CD44hi lymphoid cells in the lungs are required and sufficient to mediate the response. Thus, a subset of innate immune cells that responds to IL-33 and vigorously produces Th2-type cytokines is present in mouse lungs. These cells may provide a novel mechanism for type-2 immunity in the airways and induction of allergic airway diseases such as asthma.

The molecular mechanisms underlying the initiation of innate and adaptive proallergic Th2-type responses in the airways are not well understood. IL-33 is a new member of the IL-1 family of molecules that is implicated in Th2-type responses. Airway exposure of naive mice to a common environmental aeroallergen, the fungus Alternaria alternata, induces rapid release of IL-33 into the airway lumen, followed by innate Th2-type responses. Biologically active IL-33 is constitutively stored in the nuclei of human airway epithelial cells. Exposing these epithelial cells to A. alternata releases IL-33 extracellularly in vitro. Allergen exposure also induces acute extracellular accumulation of a danger signal, ATP; autocrine ATP sustains increases in intracellular Ca2+ concentration and releases IL-33 through activation of P2 purinergic receptors. Pharmacological inhibitors of purinergic receptors or deficiency in the P2Y2 gene abrogate IL-33 release and Th2-type responses in the Alternaria-induced airway inflammation model in naive mice, emphasizing the essential roles for ATP and the P2Y2 receptor. Thus, ATP and purinergic signaling in the respiratory epithelium are critical sensors for airway exposure to airborne allergens, and they may provide novel opportunities to dampen the hypersensitivity response in Th2-type airway diseases such as asthma.

Background-IL-33, a recently discovered IL-1 family cytokine, is implicated in the development of Th2-type responses in vivo. However, the cellular target(s) for IL-33 are poorly understood.

Background Type 2 helper T (Th2) cells have long been believed to play a pivotal role in allergic immune responses, including IgE antibody production and type 2 cytokine-mediated inflammation and pathology. A new T cell subset, T follicular helper cells (Tfh) cells, is specialized in supporting B cell maturation and antibody production. Objective To investigate the roles of Tfh cells in allergic immune responses. Methods Naïve mice were exposed to cytokines or natural allergens through the airways. Development of allergic immune responses was analyzed by collecting draining lymph nodes (LNs) and sera and by challenging the animals. Cytokine reporter mice and gene-deficient mice were used to dissect the immunologic mechanisms. Results We observed the development of IL-4-producing Tfh cells and Th2 cells in draining LNs following airway exposure to IL-1 family cytokines or natural allergens. Tfh cells and Th2 cells demonstrated unique phenotypes, tissue localization, and cytokine responses. Tfh cells supported the sustained production of IgE antibody in vivo in the absence of other T cell subsets or even when Th2 cell functions were severely compromised. Conversely, conditional deficiency of the master regulator Bcl6 in CD4+ T cells resulted in a marked reduction in Tfh cells and IgE antibody levels, but type 2 cytokine responses and eosinophilic inflammation in the airways remained unaffected. Conclusion Tfh cells play critical roles in the regulation of IgE antibody production. Allergic immune responses to airborne allergens likely involve two distinct subsets of IL-4-producing CD4+ T cells, namely Tfh cells and Th2 cells.