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.
Many human cancers are dramatically accelerated by chronic inflammation. However, the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of ...pancreatic intraepithelial neoplasia (PanIN), we found that KrasG12D induces expression of functional IL-17 receptors on PanIN epithelial cells and also stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by associated chronic pancreatitis, resulting in functional in vivo changes in PanIN epithelial gene expression. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.
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•IL-17+ T cells are recruited to the pancreas in response to Kras and inflammation•IL-17A overexpression accelerates PanIN initiation and progression•Inhibition of IL-17 signaling effectively prevents PanIN initiation and progression•Kras activates expression of functional IL-17 receptors on PanIN epithelium
McAllister et al. show that KrasG12D induces IL-17 receptors expression on PanIN epithelial cells and stimulates infiltration of IL-17-producing immune cells in a murine PanIN model, the latter of which is confirmed in human PanIN and that inhibition of IL-17 signaling prevents pancreatic neoplasia initiation.
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.
Neonatal colonization by microbes, which begins immediately after birth, is influenced by gestational age and the mother's microbiota and is modified by exposure to antibiotics. In neonates, ...prolonged duration of antibiotic therapy is associated with increased risk of late-onset sepsis (LOS), a disorder controlled by neutrophils. A role for the microbiota in regulating neutrophil development and susceptibility to sepsis in the neonate remains unclear. We exposed pregnant mouse dams to antibiotics in drinking water to limit transfer of maternal microbes to the neonates. Antibiotic exposure of dams decreased the total number and composition of microbes in the intestine of the neonates. This was associated with decreased numbers of circulating and bone marrow neutrophils and granulocyte/macrophage-restricted progenitor cells in the bone marrow of antibiotic-treated and germ-free neonates. Antibiotic exposure of dams reduced the number of interleukin-17 (IL-17)-producing cells in the intestine and production of granulocyte colony-stimulating factor (G-CSF). Granulocytopenia was associated with impaired host defense and increased susceptibility to Escherichia coli K1 and Klebsiella pneumoniae sepsis in antibiotic-treated neonates, which could be partially reversed by administration of G-CSF. Transfer of a normal microbiota into antibiotic-treated neonates induced IL-17 production by group 3 innate lymphoid cells (ILCs) in the intestine, increasing plasma G-CSF levels and neutrophil numbers in a Toll-like receptor 4 (TLR4)- and myeloid differentiation factor 88 (MyD88)-dependent manner and restored IL-17-dependent resistance to sepsis. Specific depletion of ILCs prevented IL-17- and G-CSF-dependent granulocytosis and resistance to sepsis. These data support a role for the intestinal microbiota in regulation of granulocytosis, neutrophil homeostasis and host resistance to sepsis in neonates.
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.
► Th17 cells generated by vaccination confer cross-serotype protection ► Memory Th17 cells mediate direct protection in an antigen-specific manner ► Th17 cells protect against multidrug resistant
Klebsiella challenge
TH17 cells in asthma and COPD Alcorn, John F; Crowe, Christopher R; Kolls, Jay K
Annual review of physiology,
2010, Volume:
72
Journal Article
Peer reviewed
Asthma and chronic obstructive pulmonary disease (COPD) represent two classes of chronic obstructive lung disorders that may share some similar immunologic mechanisms of disease. Asthma is a complex ...human disease characterized by airway hyperresponsiveness (AHR) and inflammation, whereas COPD is marked by progressive emphysematic changes in the lung. Recently it has been shown that advanced COPD is characterized by lymphoid follicles, drawing attention to immunological mechanisms in COPD. Despite numerous studies in mice to elucidate the immunologic mechanisms of asthma, sufficient current treatment options are limited. Clinically, many asthma patients fail to satisfactorily respond to standard steroid therapy, and this type of steroid-resistant, severe asthma has been linked to the presence of neutrophilic inflammation in the lung. The role of neutrophils, macrophages, and their secreted proteases in COPD needs to be better defined. Recently, the T lymphocyte subset T(H)17 was shown to play a role in regulating neutrophilic and macrophage inflammation in the lung, suggesting a potential role for T(H)17 cells in severe, steroid-insensitive asthma and COPD.
IL-17A was cloned more than 10 years ago and six IL-17 family members (IL-17A-F) have subsequently been described. IL-17A is largely produced by activated memory T lymphocytes but stimulates innate ...immunity and host defense. IL-17A and IL-17F both mobilize neutrophils partly through granulopoeisis and CXC chemokine induction, as well as increased survival locally. IL-17A and IL-17F production by T lymphocytes is regulated by IL-23 independent of T cell receptor activation. Increasing evidence shows that IL-17 family members play an active role in inflammatory diseases, autoimmune diseases, and cancer. This places IL-17 family members and their receptors as potential targets for future pharmacotherapy.
Interleukin-17 (IL-17) and IL-17 receptor (IL-17R) signaling are essential for regulating mucosal host defense against many invading pathogens. Commensal bacteria, especially segmented filamentous ...bacteria (SFB), are a crucial factor that drives T helper 17 (Th17) cell development in the gastrointestinal tract. In this study, we demonstrate that Th17 cells controlled SFB burden. Disruption of IL-17R signaling in the enteric epithelium resulted in SFB dysbiosis due to reduced expression of α-defensins, Pigr, and Nox1. When subjected to experimental autoimmune encephalomyelitis, IL-17R-signaling-deficient mice demonstrated earlier disease onset and worsened severity that was associated with increased intestinal Csf2 expression and elevated systemic GM-CSF cytokine concentrations. Conditional deletion of IL-17R in the enteric epithelium demonstrated that there was a reciprocal relationship between the gut microbiota and enteric IL-17R signaling that controlled dysbiosis, constrained Th17 cell development, and regulated the susceptibility to autoimmune inflammation.
•SFB-induced Th17 cell expansion in the gut controls the degree of SFB colonization•IL-17R-dependent regulation of α-defensin, Nox1, and Pigr controls SFB•Intestinal IL-17R signaling regulates dysbiosis and autoimmune inflammation.
Segmented filamentous bacteria (SFB) regulate Th17 cell development in the gastrointestinal tract. Kolls and colleagues find that intestinal IL-17R signaling regulates the abundance of the gut microbiota and SFB specifically by promoting expression of antimicrobial factors. Abrogation of intestinal IL-17R signaling results in bacterial overgrowth and enhanced susceptibility to autoimmune inflammation.
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