DCs appear to be important Selleck Olaparib regulators of the bioactivity of IL-22 as, in the gut, activated DCs produce the soluble IL-22R protein IL22BP that may play a role in the control of mucosal regeneration [109]. It is not yet clear if lung DCs

also regulate the bioactivity of IL-22 during allergen challenge. However, in a chronic model of fungal-induced asthma, IL-22 was shown to be mainly proinflammatory [110]. Over the past few years, IL-9-producing CD4+ T (Th9) cells have been identified as a subset distinct from the classical Th2 cells, with Th9 cells requiring the transcription factors IRF4, PU1, STAT6, Smad3, and Notch signaling for development. Th9 cells differentiate in response to IL-4 and TGF-β and are described to promote T-cell proliferation, IgE, and IgG production by B cells, survival and maturation of eosinophils, and mastocytosis [111-115]. Studies in asthmatic patients

have also shown elevated levels of IL-9 in the lungs after allergen challenge; this IL-9 was also demonstrated to be localized to the lymphocyte population in the BAL [116]. Initial mouse studies using transgenic lung-specific overexpression of IL-9 also showed increased airway inflammation, goblet cells metaplasia, and BHR, which were reduced when blocking IL-9 function [117, 118]. Consistent with this observation, later studies using models in which Th9 cells were adoptively transferred showed that these cells can induce allergic airway inflammation, and that this induction can be reversed by neutralization of

IL-9 [112]. IL-9 is U0126 mw also made by ILC2s and boosts production of IL-5 and IL-13, which may in turn amplify Th2-associated inflammation [23]. In a model of chronic Aspergillus-induced asthma, IL-9 neutralization suppressed the salient features of disease [119]. As for any chronic mucosal disorder, it Phosphoprotein phosphatase has been proposed that asthma might result from a (functional or absolute) deficiency in natural or induced regulatory T (Treg) cells, either through genetic predisposition, or environmental influences on homeostasis in the immune system. Studies using either the model antigen OVA or mice lacking the intronic Foxp3 enhancer CNS1 have shown that tolerance mediated by induced Foxp3+ Treg (iTreg) cells is the usual outcome after inhalation of harmless antigens [120-123]. Just like natural Treg (nTreg) cells, the iTreg cells found in the airways of mice with asthma highly express high levels of neuropilin-1, whereas iTreg cells in the LNs draining the lung of asthmatics remained neuropilin-1 low [124]. Adoptive transfer studies in mice have revealed that IL-10-producing Treg cells are able to suppress all salient features of asthma, including BHR [125, 126]. Treg cells suppress features of asthma by suppressing the activation of airway DCs (through IL-10 and TGF-β) [127], by reducing (lymph-)angiogenesis [128], and by altering the composition of the gut microbiota.