Lack of Cystic Fibrosis Transmembrane Conductance Regulator in CD3<sup>+</sup>Lymphocytes Leads to Aberrant Cytokine Secretion and Hyperinflammatory Adaptive Immune Responses

Mueller, Christian; Braag, Sofia; Keeler, Allison M.; Hodges, Craig A.; Drumm, Mitchell L.; Flotte, Terence R.

doi:10.1165/rcmb.2010-0224oc

Cited by 117 publications

(97 citation statements)

References 51 publications

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“…In addition, we report an enhanced Th2 response by BALB Cftr tm1UNC lymphocytes, which is consistent with previous data regarding enhanced cytokine secretion in lymphocytes from Cftr tm1UNC mice (20,21,41), although we detected increased IL-17 secretion from B6 Cftr tm1UNC -derived splenocytes, which differs from the profile reported by Allard et al (20). The different results might be the result of studying only CD4 + cells in contrast to splenocytes, which were evaluated here, and that the cells in Allard et al (20) were activated with CD28, which was not used to stimulate splenocytes from B6 mice in the current study.…”

Section: Discussionsupporting

confidence: 92%

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Bazett

Stefanov

Paun

et al. 2012

The Journal of Immunology

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We previously observed the lungs of naive BALB/cJ Cftrtm1UNC mice to have greater numbers of lymphocytes, by immunohistochemical staining, than did BALB wild type littermates or C57BL/6J Cftrtm1UNC mice. In the present study, we initially investigated whether this mutation in Cftr alters the adaptive immunity phenotype by measuring the lymphocyte populations in the lungs and spleens by FACS and by evaluating CD3-stimulated cytokine secretion, proliferation, and apoptosis responses. Next, we assessed a potential influence of this lymphocyte phenotype on lung function through airway resistance measures. Finally, we mapped the phenotype of pulmonary lymphocyte counts in BALB × C57BL/6J F2 Cftrtm1UNC mice and reviewed positional candidate genes. By FACS analysis, both the lungs and spleens of BALB Cftrtm1UNC mice had more CD3+ (both CD4+ and CD8+) cells than did littermates or C57BL/6J Cftrtm1UNC mice. Cftrtm1UNC and littermate mice of either strain did not differ in anti-CD3–stimulated apoptosis or proliferation levels. Lymphocytes from BALB Cftrtm1UNC mice produced more IL-4 and IL-5 and reduced levels of IFN-γ than did littermates, whereas lymphocytes from C57BL/6J Cftrtm1UNC mice demonstrated increased Il-17 secretion. BALB Cftrtm1UNC mice presented an enhanced airway hyperresponsiveness to methacholine challenge compared with littermates and C57BL/6J Cftrtm1UNC mice. A chromosome 7 locus was identified to be linked to lymphocyte numbers, and genetic evaluation of the interval suggests Itgal and Il4ra as candidate genes for this trait. We conclude that the pulmonary phenotype of BALB Cftrtm1UNC mice includes airway hyperresponsiveness and increased lymphocyte numbers, with the latter trait being influenced by a chromosome 7 locus.

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Section: Discussionsupporting

confidence: 92%

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Bazett

Stefanov

Paun

et al. 2012

The Journal of Immunology

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“…Previous studies have characterized the T cell response in human CF patients (33,34) (24,26,27,30) (35) and murine P. aeruginosa (36)(37)(38)(39)(40) or Aspergillus fumigatus infection models (41)(42)(43), providing evidence that the adaptive T cell response in CF is altered at several levels. CF T cells were found to be prone to a Th2 phenotype, with the CFTR mutation itself and/or chronic infections with P. aeruginosa as possible underlying factors (42,(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Rieber

Brand

Hector

et al. 2013

The Journal of Immunology

118

127

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Pseudomonas aeruginosa persists in patients with cystic fibrosis (CF) and drives CF lung disease progression. P. aeruginosa potently activates the innate immune system, mainly mediated through pathogen-associated molecular patterns, such as flagellin. However, the host is unable to eradicate this flagellated bacterium efficiently. The underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells generated in cancer and proinflammatory microenvironments and are capable of suppressing T cell responses. We hypothesized that P. aeruginosa induces MDSCs to escape T cell immunity. In this article, we demonstrate that granulocytic MDSCs accumulate in CF patients chronically infected with P. aeruginosa and correlate with CF lung disease activity. Flagellated P. aeruginosa culture supernatants induced the generation of MDSCs, an effect that was 1) dose-dependently mimicked by purified flagellin protein, 2) significantly reduced using flagellin-deficient P. aeruginosa bacteria, and 3) corresponded to TLR5 expression on MDSCs in vitro and in vivo. Both purified flagellin and flagellated P. aeruginosa induced an MDSC phenotype distinct from that of the previously described MDSC-inducing cytokine GM-CSF, characterized by an upregulation of the chemokine receptor CXCR4 on the surface of MDSCs. Functionally, P. aeruginosa–infected CF patient ex vivo–isolated as well as flagellin or P. aeruginosa in vitro–generated MDSCs efficiently suppressed polyclonal T cell proliferation in a dose-dependent manner and modulated Th17 responses. These studies demonstrate that flagellin induces the generation of MDSCs and suggest that P. aeruginosa uses this mechanism to undermine T cell–mediated host defense in CF and other P. aeruginosa–associated chronic lung diseases.

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“…In CF patients with P. aeruginosa infection, the prevalence of a pulmonary T H 2 immune response has been shown with higher levels of CCR4 + CD4 + (T H 2) cells, increased levels of IL-4, IL-13, and lower levels of IFN- compared with non-infected patients with CF and healthy controls (Hartl D 2005). Comparably, CF mice mounted an exaggerated IgE response upon Aspergillus fumigatus infection in the lung with increased levels of IL-4 and IL-13, mimicking both the T H 2 biased immune responses seen in CF patients (Mueller C 2010). Similar findings are also reported in studies with peripheral blood derived monocytes or whole blood cultures from CF patients infected with P. aeruginosa (Brazova J 2005, Moser C 2000.…”

Section: Lymphocytesmentioning

confidence: 52%

“…Lymphocytes from CF patients or CF mice showed a profile skewed towards T H 2 (Hartl D 2005, Mueller C 2010. In CF patients with P. aeruginosa infection, the prevalence of a pulmonary T H 2 immune response has been shown with higher levels of CCR4 + CD4 + (T H 2) cells, increased levels of IL-4, IL-13, and lower levels of IFN- compared with non-infected patients with CF and healthy controls (Hartl D 2005).…”

Section: Lymphocytesmentioning

confidence: 99%

Immune Dysfunction in Cystic Fibrosis

Xu¹,

Worgall²

2012

Cystic Fibrosis - Renewed Hopes Through Research

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Lack of Cystic Fibrosis Transmembrane Conductance Regulator in CD3⁺Lymphocytes Leads to Aberrant Cytokine Secretion and Hyperinflammatory Adaptive Immune Responses

Cited by 117 publications

References 51 publications

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Immune Dysfunction in Cystic Fibrosis

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Lack of Cystic Fibrosis Transmembrane Conductance Regulator in CD3+Lymphocytes Leads to Aberrant Cytokine Secretion and Hyperinflammatory Adaptive Immune Responses

Cited by 117 publications

References 51 publications

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Immune Dysfunction in Cystic Fibrosis

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Product

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Lack of Cystic Fibrosis Transmembrane Conductance Regulator in CD3⁺Lymphocytes Leads to Aberrant Cytokine Secretion and Hyperinflammatory Adaptive Immune Responses