Reduced mucosal associated invariant T-cells are associated with increased disease severity and Pseudomonas aeruginosa infection in cystic fibrosis.

Daniel J Smith,Geoffrey R Hill,Scott C Bell,David W Reid,Johan K Sandberg

doi:10.1371/journal.pone.0109891

Abstract

BackgroundPrimary defects in host immune responses have been hypothesised to contribute towards an inability of subjects with cystic fibrosis (CF) to effectively clear pulmonary infections. Innate T-lymphocytes provide rapid pathogen-specific responses prior to the development of classical MHC class I and II restricted T-cell responses and are essential to the initial control of pulmonary infection. We aimed to examine the relationship between peripheral blood lymphocyte phenotype and clinical outcomes in adults with CF.MethodsWe studied 41 subjects with CF and 22, age matched, non-smoking healthy control subjects. Lymphocytes were extracted from peripheral blood samples and phenotyped by flow-cytometry. Lymphocyte phenotype was correlated with sputum microbiology and clinical parameters.ResultsIn comparison to healthy control subjects, mucosal associated invariant T (MAIT)-lymphocytes were significantly reduced in the peripheral blood of subjects with CF (1.1% versus 2.0% of T-lymphocytes, P = 0.002). MAIT cell concentration was lowest in CF subjects infected with P. aeruginosa and in subjects receiving treatment for a pulmonary exacerbation. Furthermore a reduced MAIT cell concentration correlated with severity of lung disease.ConclusionReduced numbers of MAIT cells in subjects with CF were associated with P. aeruginosa pulmonary infection, pulmonary exacerbations and more severe lung disease. These findings provide the impetus for future studies examining the utility of MAIT cells in immunotherapies and vaccine development. Longitudinal studies of MAIT cells as biomarkers of CF pulmonary infection are awaited.

Highlights

Cystic fibrosis (CF) pulmonary disease is typified by a vicious cycle of bacterial infection and exuberant, but ineffective host immune response [1]
Comparison of lymphocyte sub-sets between groups, demonstrated a reduction in the percentage of mucosal associated invariant T (MAIT) cells in subjects with cystic fibrosis (CF), compared to healthy controls, with an accompanying increase in the percentage of c/d T-cells
In this study we demonstrate for the first time that the peripheral blood of subjects with CF is characterized by a relative lymphopenia and major reductions in circulating MAIT cells and to a lesser extent an increase in c/d T-cells compared to normal healthy controls, consistent with both quantitative and qualitative differences in innate T-cell immunity in CF

Summary

Introduction

Cystic fibrosis (CF) pulmonary disease is typified by a vicious cycle of bacterial infection and exuberant, but ineffective host immune response [1]. The inability of the intense inflammatory response to clear infection has led to speculation that intrinsic immune defects may contribute to the persistence of pathogens in CF [2]. Studies of peripheral, adaptive immune responses in CF have largely focused on the classic dichotomy of T-helper (Th)-1 and Th-2 responses [4]. These early studies suggested a skew towards a. Primary defects in host immune responses have been hypothesised to contribute towards an inability of subjects with cystic fibrosis (CF) to effectively clear pulmonary infections.

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