Regulatory T-Cell Impairment in Cystic Fibrosis Patients with Chronic Pseudomonas Infection

Hector, Andreas; Schäfer, Heike; Pöschel, Simone; Fischer, Alexandra; Fritzsching, Benedikt; Ralhan, Anjali; Carevic, Melanie; Öz, Hasan Halit; Zundel, Sabine; Hogardt, Michael; Bakele, Martina; Rieber, Nikolaus; Riethmueller, J.; Graepler-Mainka, Ute; Stahl, Mirjam; Bender, Annika; Frick, Julia-Stefanie; Mall, Marcus; Hartl, Dominik

doi:10.1164/rccm.201407-1381oc

Cited by 78 publications

(83 citation statements)

References 42 publications

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“…The importance of Th17 immunity is highlighted by a study from Chan and colleagues (59) showing enhanced antigenspecific Th17 responses in draining lymph nodes of explanted lungs of patients with CF, suggesting that this subset may be important for lung immunity. Patients chronically sputum PA culture positive show a trend to reduced systemic FoxP3 and IL-10 transcription, compatible with the notion that defects in immune regulation may contribute to an inflammatory environment that facilitates PA lung infection (60). It has become apparent that chronic immune stimulation, commonly by tumor antigens or viral antigens, can lead to an "exhausted" T-cell phenotype, characterized by raised expression of programmed cell death-1 (61).…”

Section: Original Article Discussionsupporting

confidence: 59%

Chronic Infection by Mucoid Pseudomonas aeruginosa Associated with Dysregulation in T-Cell Immunity to Outer Membrane Porin F

Quigley

Reynolds

Goudet

et al. 2015

Am J Respir Crit Care Med

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Rationale: Pseudomonas aeruginosa (PA) is an environmental pathogen that commonly infects individuals with cystic fibrosis (CF) and non-CF bronchiectasis, impacting morbidity and mortality. To understand the pathobiology of interactions between the bacterium and host adaptive immunity and to inform rational vaccine design, it is important to understand the adaptive immune correlates of disease.Objectives: To characterize T-cell immunity to the PA antigen outer membrane porin F (OprF) by analyzing immunodominant epitopes in relation to infection status.Methods: Patients with non-CF bronchiectasis were stratified by frequency of PA isolation. T-cell IFN-g immunity to OprF and its immunodominant epitopes was characterized. Patterns of human leukocyte antigen (HLA) restriction of immunodominant epitopes were defined using HLA class II transgenic mice. Immunity was characterized with respect to cytokine and chemokine secretion, antibody response, and T-cell activation transcripts. Measurements and Main Results:Patients were stratified according to whether PA was never, sometimes (,50%), or frequently (>50%) isolated from sputum. Patients with frequent PA sputumpositive isolates were more likely to be infected by mucoid PA, and they showed a narrow T-cell epitope response and a relative reduction in Th1 polarizing transcription factors but enhanced immunity with respect to antibody production, innate cytokines, and chemokines. Conclusions:We have defined the immunodominant, HLArestricted T-cell epitopes of OprF. Our observation that chronic infection is associated with a response of narrowed specificity, despite strong innate and antibody immunity, may help to explain susceptibility in these individuals and pave the way for better vaccine design to achieve protective immunity.

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Section: Original Article Discussionsupporting

confidence: 59%

Chronic Infection by Mucoid Pseudomonas aeruginosa Associated with Dysregulation in T-Cell Immunity to Outer Membrane Porin F

Quigley

Reynolds

Goudet

et al. 2015

Am J Respir Crit Care Med

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“…The mouse model of acute pulmonary Pseudomonas aeruginosa infection was performed as published recently by our group [22]. Mice were infected intranasally with Pseudomonas aeruginosa (PAO1) with doses ranging from 2×10 5 to 2×10 6 CFU using established procedures [22].…”

Section: Methodsmentioning

confidence: 99%

“…Mice were infected intranasally with Pseudomonas aeruginosa (PAO1) with doses ranging from 2×10 5 to 2×10 6 CFU using established procedures [22]. Infections were carried out under antagonizable anesthesia.…”

Section: Methodsmentioning

confidence: 99%

CXCR1 Regulates Pulmonary Anti-Pseudomonas Host Defense

et al. 2016

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Pseudomonas aeruginosa is a key opportunistic pathogen causing disease in cystic fibrosis (CF) and other lung diseases such as chronic obstructive pulmonary disease (COPD). However, the pulmonary host defense mechanisms regulating anti-P. aeruginosa immunity remain incompletely understood. Here we demonstrate, by studying an airway P. aeruginosa infection model, in vivo bioluminescence imaging, neutrophil effector responses and human airway samples, that the chemokine receptor CXCR1 regulates pulmonary host defense against P. aeruginosa. Mechanistically, CXCR1 regulates anti-Pseudomonas neutrophil responses through modulation of reactive oxygen species and interference with Toll-like receptor 5 expression. These studies define CXCR1 as a novel, noncanonical chemokine receptor that regulates pulmonary anti-Pseudomonas host defense with broad implications for CF, COPD and other infectious lung diseases.

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“…Tregs isolated from CF patients or from cftr−/− mice showed reduced functional suppressive activity compared with Tregs from non-CF controls. Both “extrinsic” P. aeruginosa -induced effects and “intrinsic” CFTR-mediated Treg functional skewing contributed to Treg impairment in CF [203]. Th17 cells, through IL-17 production, may also be involved in CF-related diabetes (CFRD) [204].…”

Section: Roscovitine and Cystic Fibrosismentioning

confidence: 99%

Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

et al. 2016

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(R)-Roscovitine, a pharmacological inhibitor of kinases, is currently in phase II clinical trial as a drug candidate for the treatment of cancers, Cushing's disease and rheumatoid arthritis. We here review the data that support the investigation of (R)-roscovitine as a potential therapeutic agent for the treatment of cystic fibrosis (CF). (R)-Roscovitine displays four independent properties that may favorably combine against CF: (1) it partially protects F508del-CFTR from proteolytic degradation and favors its trafficking to the plasma membrane; (2) by increasing membrane targeting of the TRPC6 ion channel, it rescues acidification in phagolysosomes of CF alveolar macrophages (which show abnormally high pH) and consequently restores their bactericidal activity; (3) its effects on neutrophils (induction of apoptosis), eosinophils (inhibition of degranulation/induction of apoptosis) and lymphocytes (modification of the Th17/Treg balance in favor of the differentiation of anti-inflammatory lymphocytes and reduced production of various interleukins, notably IL-17A) contribute to the resolution of inflammation and restoration of innate immunity, and (4) roscovitine displays analgesic properties in animal pain models. The fact that (R)-roscovitine has undergone extensive preclinical safety/pharmacology studies, and phase I and II clinical trials in cancer patients, encourages its repurposing as a CF drug candidate.

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Regulatory T-Cell Impairment in Cystic Fibrosis Patients with Chronic Pseudomonas Infection

Cited by 78 publications

References 42 publications

Chronic Infection by Mucoid Pseudomonas aeruginosa Associated with Dysregulation in T-Cell Immunity to Outer Membrane Porin F

Chronic Infection by Mucoid Pseudomonas aeruginosa Associated with Dysregulation in T-Cell Immunity to Outer Membrane Porin F

CXCR1 Regulates Pulmonary Anti-<b><i>Pseudomonas</i></b> Host Defense

Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

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