Steroid-resistant asthma comprises an important source of morbidity in patient populations. TH17 cells represent a distinct population of CD4+ Th cells that mediate neutrophilic inflammation and are characterized by the production of IL-17, IL-22, and IL-6. To investigate the function of TH17 cells in the context of Ag-induced airway inflammation, we polarized naive CD4+ T cells from DO11.10 OVA-specific TCR-transgenic mice to a TH2 or TH17 phenotype by culturing in conditioned medium. In addition, we also tested the steroid responsiveness of TH2 and TH17 cells. In vitro, TH17 cytokine responses were not sensitive to dexamethasone (DEX) treatment despite immunocytochemistry confirming glucocorticoid receptor translocation to the nucleus following treatment. Transfer of TH2 cells to mice challenged with OVA protein resulted in lymphocyte and eosinophil emigration into the lung that was markedly reduced by DEX treatment, whereas TH17 transfer resulted in increased CXC chemokine secretion and neutrophil influx that was not attenuated by DEX. Transfer of TH17 or TH2 cells was sufficient to induce airway hyperresponsiveness (AHR) to methacholine. Interestingly, AHR was not attenuated by DEX in the TH17 group. These data demonstrate that polarized Ag-specific T cells result in specific lung pathologies. Both TH2 and TH17 cells are able to induce AHR, whereas TH17 cell-mediated airway inflammation and AHR are steroid resistant, indicating a potential role for TH17 cells in steroid-resistant asthma.

IL-17R signaling is critical for pulmonary neutrophil recruitment and host defense against Gram-negative bacteria through the coordinated release of G-CSF and CXC chemokine elaboration. In this study, we show that IL-17R is localized to basal airway cells in human lung tissue, and functional IL-17R signaling occurs on the basolateral surface of human bronchial epithelial (HBE) cells. IL-17A and IL-17F were potent inducers of growth-related oncogene-α and G-CSF in HBE cells, and significant synergism was observed with TNF-α largely due to signaling via TNFRI. The activities of both IL-17A and IL-17F were blocked by a specific anti-IL-17R Ab, but only IL-17A was blocked with a soluble IL-17R, suggesting that cell membrane IL-17R is required for signaling by both IL-17A and IL-17F. Because IL-17A and IL-17F both regulate lung neutrophil recruitment, we measured these molecules as well as the proximal regulator IL-23p19 in the sputum of patients with cystic fibrosis (CF) undergoing pulmonary exacerbation. We found significantly elevated levels of these molecules in the sputum of patients with CF who were colonized with Pseudomonas aeruginosa at the time of pulmonary exacerbation, and the levels declined with therapy directed against P. aeruginosa. IL-23 and the downstream cytokines IL-17A and IL-17F are critical molecules for proinflammatory gene expression in HBE cells and are likely involved in the proinflammatory cytokine network involved with CF pathogenesis.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease of unknown etiology that results in

Indoleamine 2,3 dioxygenase (IDO) has emerged as an important mediator of immune tolerance via inhibition of Th1 responses. However, the role of IDO in antigen-induced tolerance or allergic inflammation in the airways that is regulated by Th2 responses has not been elucidated. By using IDO ؊/؊ mice, we found no impairment of airway tolerance, but, surprisingly, absence of IDO provided significant relief from establishment of allergic airways disease, as evident from attenuated Th2 cytokine production, airway inflammation, mucus secretion, airway hyperresponsiveness, and serum ovalbumin-specific IgE. Myeloid dendritic cells isolated from lung-draining lymph nodes of mice immunized for either Th1 or Th2 response revealed fewer mature dendritic cells in the lymph nodes of IDO ؊/؊ mice. However, the net functional impact of IDO deficiency on antigen-induced responses was more remarkable in the Th2 model than in the Th1 model. Collectively, these data suggest that IDO is not required for the induction of immune tolerance in the airways but plays a role in promoting Th2-mediated allergic airway inflammation via unique effects on lung dendritic cells.tryptophan ͉ DC ͉ airways ͉ asthma I ndoleamine 2,3 dioxygenase (IDO) is an enzyme that mediates tryptophan catabolism into its metabolites including kynurenine or quinolinic acid (1-3). IDO protein is widely expressed in a variety of cell types including B cells, macrophages, eosinophils, dendritic cells (DCs), endothelial cells, and many types of tumor cells (2, 4-9). Because products of tryptophan metabolism are required for normal cell growth, depletion of IDO adversely impacts cell function (10). In the last decade, IDO has emerged as an important negative regulator in the immune system primarily because of its function in DCs, which play a quintessential role in antigen presentation to T cells (11). Several studies have implicated IDO in tumor-associated immune tolerance, and IDO has been associated with inhibition of Th1-mediated disease states (7,(11)(12)(13)(14)(15). Although IDO has been generally associated with Th1 inhibition, Trp metabolites were shown to induce Th2-like regulatory cells that suppressed Th1 pathology in experimental autoimmune encephalomyelitis, an experimental model for multiple sclerosis (14). Despite suggestion of differential effects of IDO on Th1 versus Th2 cells in these reports, no study has sufficiently explored this concept.There is little doubt that IDO plays a role in immune suppression and induction of T cell anergy. However, it has not been fully evaluated whether IDO-mediated immune suppression is pervasive under all circumstances. We investigated the role of IDO in established models of antigen-induced airway tolerance and inflammation by using IDO-deficient mice. We found that lack of IDO does not impair induction of immune tolerance induced by repeated antigen inhalation. On the contrary, IDO deficiency significantly attenuated the Th2 phenotype in the lungs in response to allergen provocation. When WT and IDO Ϫ/Ϫ mice were im...

Immunotherapy against a variety of malignancies, including pleural-based malignancies, has shown promise in animal models and early human clinical trials, but successful efforts will need to address immunosuppressive factors of the tumor and host, particularly certain cytokines and CD4(+) CD25(+) regulatory T cells (Treg). Here, we evaluated the cellular and cytokine components of malignant pleural effusions from 44 patients with previously diagnosed mesothelioma, non-small cell lung cancer (NSCLC), or breast cancer and found significant differences in the immune profile of pleural effusions secondary to mesothelioma vs. carcinoma. Although a high prevalence of functionally suppressive CD4(+) CD25(+) T cells was found in carcinomatous pleural effusions, mesothelioma pleural effusions contained significantly fewer CD4(+) CD25(+) T cells. Activated CD8(+) T cells in pleural fluid were significantly more prevalent in mesothelioma than carcinoma. However, there is clear patient-to-patient variability and occasional mesothelioma patients with high percentages of CD4(+) CD25(+) pleural effusion T cells and low percentages of CD8(+) CD25(+) pleural effusion T cells can be identified. Mesothelioma pleural effusions contained the highest concentrations of the immunosuppressive cytokine transforming growth factor (TGF)-beta. Thus, the contribution of cellular and cytokine components of immunosuppression associated with malignant pleural effusions varies by tumor histology and by the individual patient. These results have implications for the development of immunotherapy directed to the malignant pleural space, and suggest the need to tailor immunotherapy to overcome immunosuppressive mechanisms in tumor environments.

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Rationale IL-17 is a proinflammatory cytokine that enhances neutrophil recruitment in response to allergen in murine lung. In an Aspergillus fumigatus (Af)-induced asthma model, wild-type C57BL/6 mice develop bronchial inflammation and hyperreactivity. We hypothesized that, compared to C57BL/6, Af sensitized IL-17R KO mice would have reduced neutrophil recruitment to the lung, airway resistance and hyperreactivity. Methods C57BL/6 and IL-17R KO male mice, 6–8 wk old, were sensitized intraperitoneally with 40 ug Af extract and 2 mg Al(OH)3 on days 0 and 7, and intratracheally with 25 ug Af on days 21, 22, and 23. Bronchoalveolar lavage (BAL) differential cell counts and cytokine analysis were done at 24 and 72 hr. Flexivent was performed at 24 hr to assess airway physiology. Results WT mice had significant influx of both neutrophils and eosinophils in response to Af at 24 hr. In contrast, IL-17R KO mice showed reduced neutrophil and eosinophil emigration to the lung which was associated with lower KC and eotaxin levels in BAL fluid. Furthermore, Flexivent data showed lower airway resistance and bronchial hyperreactivity in IL-17R KO mice. Conclusion Our findings in Af treated IL-17R KO mice of decreased pulmonary neutrophil and eosinophil recruitment at 24 hr suggest that IL-17 promotes granulocyte recruitment as well as airway hyperreactivity. Funding: NHLBI