Severe respiratory syncytial virus (RSV) infections are characterized by airway epithelial cell damage, mucus hypersecretion, and Th2 cytokine production. Less is known about the role of IL-17. We observed increased IL-6 and IL-17 levels in tracheal aspirate samples from severely ill infants with RSV infection. In a mouse model of RSV infection, time-dependent increases in pulmonary IL-6, IL-23, and IL-17 expression were observed. Neutralization of IL-17 during infection and observations from IL-17(-/-) knockout mice resulted in significant inhibition of mucus production during RSV infection. RSV-infected animals treated with anti-IL-17 had reduced inflammation and decreased viral load, compared with control antibody-treated mice. Blocking IL-17 during infection resulted in significantly increased RSV-specific CD8 T cells. Factors associated with CD8 cytotoxic T lymphocytes, T-bet, IFN-γ, eomesodermin, and granzyme B were significantly up-regulated after IL-17 blockade. Additionally, in vitro analyses suggest that IL-17 directly inhibits T-bet, eomesodermin, and IFN-γ in CD8 T cells. The role of IL-17 was also investigated in RSV-induced exacerbation of allergic airway responses, in which neutralization of IL-17 led to a significant decrease in the exacerbated disease, including reduced mucus production and Th2 cytokines, with decreased viral proteins. Taken together, our data demonstrate that IL-17 plays a pathogenic role during RSV infections.

The response to respiratory syncytial virus (RSV), negative strand ssRNA virus, depends upon the ability to recognize specific pathogen-associated targets. In the current study, the role of TLR7 that recognizes ssRNA was examined. Using TLR7−/− mice, we found that the response to RSV infection in the lung was more pathogenic as assessed by significant increases in inflammation and mucus production. Although there appeared to be no effect of TLR7 deficiency on type I IFN, the pathology was associated with an alteration in T cell responses with increases in mucogenic cytokines IL-4, IL-13, and IL-17. Examination of dendritic cells from TLR7−/− animals indicated a preferential activation of IL-23 (a Th17-promoting cytokine) and a decrease in IL-12 production. Neutralization of IL-17 in the TLR7−/− mice resulted in a significant decrease in the mucogenic response in the lungs of the RSV-infected mice. Thus, without TLR7-mediated responses, an altered immune environment ensued with a significant effect on airway epithelial cell remodeling and goblet cell hyper/metaplasia, leading to increased mucus production.

One of the more insidious outcomes of patients who survive severe sepsis is profound immunosuppression. In this study, we addressed the hypothesis that post septic immune defects were due, in part, to the presence and/or expansion of regulatory T cells (Tregs). After recovery from severe sepsis, mice exhibited significantly higher numbers of Tregs, which exerted greater in vitro suppressive activity compared with controls. The expansion of Tregs was not limited to CD25 ؉ cells, because Foxp3 expression was also detected in CD25 ؊ cells from post septic mice. This latter group exhibited a significant increase of chromatin remodeling at the Foxp3 promoter, because a marked increase in acetylation at H3K9 was associated with an increase in IntroductionSepsis is a growing health concern, which is responsible for approximately 250 000 deaths a year in the United States. 1 Most patients who survive life-threatening systemic inflammatory response syndrome develop a sustained immunosuppressive state, referred to as compensatory anti-inflammatory response syndrome. It is becoming clear that compensatory anti-inflammatory response syndrome is actually a protracted immunosuppressive state in post septic patients, which may last for years. 2 The immunoregulation in these patients is associated with both the inability to eradicate a primary infection and the development of new secondary infections. 3 The question remains: why does "immunoparalysis" persist in the post septic immune system? Experimental polymicrobial sepsis is characterized by dysfunction of dendritic cells (DCs), 3 monocytes, 4 and T lymphocytes 5 during both phases of the response syndrome. Recent experiments have focused on understanding the presence and function of regulatory T cells (Tregs) during experimental and clinical sepsis. 6,7 An increased percentage of Tregs has been observed in the circulation of patients with septic shock, and the persistence of increased Tregs has been associated with a poor long-term prognosis. 7 Thus, the role of Tregs during and after sepsis needs fuller exploration.The transcription factor Foxp3 is a specific lineage marker for Tregs in mice, which is known to be a key regulator of Treg-cell development, survival, and function. 8 Importantly, there is evidence that naive/conventional CD4 ϩ CD25 Ϫ Foxp3 Ϫ cells convert extrathymically into regulatory Foxp3 ϩ T cells under certain conditions, including those associated with tumor development, 9 the intestinal immune system, 10 and in the allergic lung. 11 The mechanisms driving the conversion of Tregs under homeostatic or pathogenic conditions has been extensively studied, and the secretion of cytokines, especially interleukin-10 (IL-10), by DCs have an important role in the differentiation of CD4 ϩ T cells into Tregs. 12 One consequence of Treg conversion involves epigenetic regulation of the Foxp3 promoter. 13 In fact, the Foxp3 promoter showed a stronger association with acetylated histones in Tregs than in conventional T cells, suggesting that the Foxp3 promoter is rea...

BackgroundRespiratory syncytial virus (RSV) infects nearly all infants by age 2 and is a leading cause of bronchiolitis. RSV may employ several mechanisms to induce immune dysregulation, including dendritic cell (DC) modulation during the immune response to RSV.Methods and FindingsExpansion of cDC and pDC by Flt3L treatment promoted an anti-viral response with reduced pathophysiology characterized by decreased airway hyperreactivity, reduced Th2 cytokines, increased Th1 cytokines, and a reduction in airway inflammation and mucus overexpression. These protective aspects of DC expansion could be completely reversed by depleting pDCs during the RSV infection. Expansion of DCs by Flt3L treatment enhanced in CD8+ T cell responses, which was reversed by depletion of pDC.ConclusionsThese results indicate that a balance between cDC and pDC in the lung and its lymph nodes is crucial for the outcome of a pulmonary infection. Increased pDC numbers induced by Flt3L treatment have a protective impact on the nature of the overall immune environment.