Kong Chen

Critical Role of IL-17RA in Immunopathology of Influenza Infection

Acute lung injury due to influenza infection is associated with high mortality, an increase in neutrophils in the airspace, and increases in tissue myeloperoxidase (MPO). Because IL-17A and IL-17F, ligands for IL-17 receptor antagonist (IL-17RA), have been shown to mediate neutrophil migration into the lung in response to LPS or Gram-negative bacterial pneumonia, we hypothesized that IL-17RA signaling was critical for acute lung injury in response to pulmonary influenza infection. IL-17RA was critical for weight loss and both neutrophil migration and increases in tissue myeloperoxidase (MPO) after influenza infection. However, IL-17RA was dispensable for the recruitment of CD8+ T cells specific for influenza hemagglutinin or nucleocapsid protein. Consistent with this, IL-17RA was not required for viral clearance. However, in the setting of influenza infection, IL-17RA−/− mice showed significantly reduced levels of oxidized phospholipids, which have previously been shown to be an important mediator in several models of acute lung injury, including influenza infection and gastric acid aspiration. Taken together, these data support targeting IL-17 or IL-17RA in acute lung injury due to acute viral infection.

IL-17RA Is Required for CCL2 Expression, Macrophage Recruitment, and Emphysema in Response to Cigarette Smoke

Chronic Obstructive Pulmonary Disease (COPD) is characterized by airspace enlargement and peribronchial lymphoid follicles; however, the immunological mechanisms leading to these pathologic changes remain undefined. Here we show that cigarette smoke is a selective adjuvant that augments in vitro and in vivo Th17, but not Th1, cell differentiation via the aryl hydrocarbon receptor. Smoke exposed IL-17RA−/− mice failed to induce CCL2 and MMP12 compared to WT mice. Remarkably, in contrast to WT mice, IL-17RA−/− mice failed to develop emphysema after 6 months of cigarette smoke exposure. Taken together, these data demonstrate that cigarette smoke is a potent Th17 adjuvant and that IL-17RA signaling is required for chemokine expression necessary for MMP12 induction and tissue emphysema.

Th17 Cells Mediate Clade-Specific, Serotype-Independent Mucosal Immunity

The interleukin-17 (IL-17) family of cytokines phylogenetically predates the evolution of T cells in jawed vertebrates, suggesting that the ontogeny of the Th17 cell lineage must have arisen to confer an evolutionary advantage to the host over innate sources of IL-17. Utilizing a model of mucosal immunization with the encapsulated bacteria Klebsiella pneumoniae, we found that B cells, which largely recognized polysaccharide capsular antigens, afforded protection to only the vaccine strain. In contrast, memory Th17 cells proliferated in response to conserved outer membrane proteins and conferred protection against several serotypes of K. pneumoniae, including the recently described multidrug resistant New Dehli metallolactamase strain. Notably, this heterologous, clade-specific protection was antibody independent, demonstrating the Th17 cell lineage confers a host advantage by providing heterologous mucosal immunity independent of serotype-specific antibody.

T Cell–Mediated Host Immune Defenses in the Lung

Evidence has increasingly shown that the lungs are a major site of immune regulation. A robust and highly regulated immune response in the lung protects the host from pathogen infection, whereas an inefficient or deleterious response can lead to various pulmonary diseases. Many cell types, such as epithelial cells, dendritic cells, macrophages, neutrophils, eosinophils, and B and T lymphocytes, contribute to lung immunity. This review focuses on the recent advances in understanding how T lymphocytes mediate pulmonary host defenses against bacterial, viral, and fungal pathogens.

Conserved natural IgM antibodies mediate innate and adaptive immunity against the opportunistic fungus Pneumocystis murina

Natural IgM antibodies in diverse species recognize conserved carbohydrates in fungal cell walls and influence early host defense against Pneumocystis in mice.

Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling

MDSC-derived nitric oxide supports the development of Th17 cells in ovarian cancer dependent on the induction of endogenous NOS2 and the cGMP–cGK pathway in Th17 cells.

Patients with cystic fibrosis have inducible IL-17+IL-22+ memory cells in lung draining lymph nodes.

BACKGROUND IL-17 is an important cytokine signature of the TH differentiation pathway TH17. This T-cell subset is crucial in mediating autoimmune disease or antimicrobial immunity in animal models, but its presence and role in human disease remain to be completely characterized. OBJECTIVE We set out to determine the frequency of TH17 cells in patients with cystic fibrosis (CF), a disease in which there is recurrent infection with known pathogens. METHODS Explanted lungs from patients undergoing transplantation or organ donors (CF samples=18; non-CF, nonbronchiectatic samples=10) were collected. Hilar nodes and parenchymal lung tissue were processed and examined for TH17 signature by using immunofluorescence and quantitative real-time PCR. T cells were isolated and stimulated with antigens from Pseudomonas aeruginosa and Aspergillus species. Cytokine profiles and staining with flow cytometry were used to assess the reactivity of these cells to antigen stimulation. RESULTS We found a strong IL-17 phenotype in patients with CF compared with that seen in control subjects without CF. Within this tissue, we found pathogenic antigen-responsive CD4+IL-17+ cells. There were double-positive IL-17+IL-22+ cells [TH17(22)], and the IL-22+ population had a higher proportion of memory characteristics. Antigen-specific TH17 responses were stronger in the draining lymph nodes compared with those seen in matched parenchymal lungs. CONCLUSION Inducible proliferation of TH17(22) with memory cell characteristics is seen in the lungs of patients with CF. The function of these individual subpopulations will require further study regarding their development. T cells are likely not the exclusive producers of IL-17 and IL-22, and this will require further characterization.

Th17 cell based vaccines in mucosal immunity

Vaccination is proven to be effective in controlling many infections including small pox, influenza and hepatitis, but strain-specific factors may limit vaccine efficacy. All of these vaccines work through the generation of neutralizing antibodies but for some pathogens there may be roles for serotype-independent immunity. Recently several groups using murine vaccine models have shown that induced T helper cell responses including Th17 responses have shown the potential for CD4+ T-cell dependent vaccine responses. Th17 mediated protective responses involve the recruitment of neutrophils, release of anti-microbial peptides and IL-17-driven Th1 immunity. These effector mechanisms provide immunity against a range of pathogens including the recently described antibiotic-resistant metallo-beta-lactamase 1 Klebsiella pneumoniae. Continued elucidation of the mechanism of Th17 responses and identification of effective adjuvants for inducing robust non pathogenic Th17 responses may lead to successful Th17 based vaccines. Here we summarize the recent advances in understanding the role of Th17 in vaccine induced immunity. We also discuss the current status and future challenges in Th17-based mucosal vaccine development.

Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation

Gut reasons to brush your teeth Some gut conditions, such as inflammatory bowel disease (IBD), ulcerative colitis, and Crohns disease (CD), are associated with imbalances in the gut microbe community. The causes of these intractable diseases have been difficult to discern. Atarashi et al. took samples from the mouths of IBD and CD patients and inoculated the extracted bacteria into germ-free mice (see the Perspective by Cao). Some of the inoculated mice showed strong proliferation of T helper 1 cells associated with the establishment of oral Klebsiella species in the colon. Klebsiella can be resistant to multiple antibiotics and are able to replace normal colon microbes after antibiotic therapy. Now we know that they probably originate from the mouth and could potentially contribute to bowel disease. Science, this issue p. 359; see also p. 308 The mouth may act as a reservoir for intestinal disease-causing bacteria. Intestinal colonization by bacteria of oral origin has been correlated with several negative health outcomes, including inflammatory bowel disease. However, a causal role of oral bacteria ectopically colonizing the intestine remains unclear. Using gnotobiotic techniques, we show that strains of Klebsiella spp. isolated from the salivary microbiota are strong inducers of T helper 1 (TH1) cells when they colonize in the gut. These Klebsiella strains are resistant to multiple antibiotics, tend to colonize when the intestinal microbiota is dysbiotic, and elicit a severe gut inflammation in the context of a genetically susceptible host. Our findings suggest that the oral cavity may serve as a reservoir for potential intestinal pathobionts that can exacerbate intestinal disease.

Pulmonary Th17 Antifungal Immunity Is Regulated by the Gut Microbiome

Commensal microbiota are critical for the development of local immune responses. In this article, we show that gut microbiota can regulate CD4 T cell polarization during pulmonary fungal infections. Vancomycin drinking water significantly decreased lung Th17 cell numbers during acute infection, demonstrating that Gram-positive commensals contribute to systemic inflammation. We next tested a role for RegIIIγ, an IL-22–inducible antimicrobial protein with specificity for Gram-positive bacteria. Following infection, increased accumulation of Th17 cells in the lungs of RegIIIγ−/− and Il22−/− mice was associated with intestinal segmented filamentous bacteria (SFB) colonization. Although gastrointestinal delivery of rRegIIIγ decreased lung inflammatory gene expression and protected Il22−/− mice from weight loss during infection, it had no direct effect on SFB colonization, fungal clearance, or lung Th17 immunity. We further show that vancomycin only decreased lung IL-17 production in mice colonized with SFB. To determine the link between gut microbiota and lung immunity, serum-transfer experiments revealed that IL-1R ligands increase the accumulation of lung Th17 cells. These data suggest that intestinal microbiota, including SFB, can regulate pulmonary adaptive immune responses.