In humans, systemic T-cell responses to allergens in healthy individuals are dominated by TGF-β and/or IL-10. Asthmatic children have reductions in the numbers of pulmonary Foxp3+ Treg cells, whereas the number of PLX4032 cell line Treg cells inside the allergen-challenged adult lung is clearly enhanced. This suggests that the function of Treg cells might be suppressed

in adults with asthma [130, 131]. TNF-α, IL-6, and TSLP are all overproduced in asthmatic airways and could be responsible for inhibiting the function of Treg cells [132]. The exact mechanism by which Treg cells are induced and recruited to the lungs of asthmatic patients and mouse models of asthma is being intensely studied. Initially, it was shown that DCs expressing ICOS-L and IL-10 were critical for inducing iTreg cells [133, 134]. It was also proposed that plasmacytoid DCs are necessary for Treg-cell

formation and/or expansion in the lungs [39, 135]. Recently, Siglec-F+ alveolar macrophages were found to be the major APC driving the differentiation of Foxp3+ Treg cells in the lungs of mice following allergen inhalation, in a process requiring TGF-β and the retinal dehydrogenases, RALDH-1 and RALDH-2) [136]. The means by which Treg cells become attracted to the allergically PXD101 in vitro inflamed lungs and LNs of mice involves the CCR4 and CCR7 receptor, respectively [137]. The main source of the CCR4 ligands, CCL17 and CCL22, is the CD103+ cDC subset of the lungs [34] and targeting antigens to these sDCs using a Ag-conjugated CD103 moAb has been shown to lead to the expansion and/or accumulation of Treg cells in the lungs [138]. The exact contribution of the intestinal (or pulmonary) microbiota to the induction of Treg cells in the gut and/or lungs is another topic of great interest. Several experiments have now shown that germ-free

mice or mice treated with broad-spectrum antibiotics at a very young age have increased features of allergic disease, including increased numbers of basophils and NKT cells [139-143]. These treatments also affect the lung microbiota, but we do not understand the full impact of this on asthma at present [144]. It is possible that the airway microbiota also regulate the threshold for epithelial Tideglusib and immune cell TLR activation, just as the gut microbiota does in colonic epithelium. Given the clear evidence for IL-4 and/or IL-13 in mouse models of allergic disease, and the presence of Th2 cytokines in patients with asthma, several clinical trials with inhibitors of these cytokines have been launched. A humanized anti-IL-4 neutralizing antibody (pascolizumab) showed promising results in human-derived cell lines and monkeys [145]. However, IL-4-specific antagonists (the IL-4 variant pitrakinra) used in clinical trials have failed to show convincing clinical results [146]. For IL-13, several neutralizing antibodies have been developed (IMA-638, AMG317 (lebrikizumab), and CAT-354), but trials are still in their infancy.