Intrinsic predisposition of naïve cystic fibrosis T cells to differentiate towards a Th17 phenotype

Rahul Kushwah,Neil B Sweezey,Stéphane Gagnon

doi:10.1186/1465-9921-14-138

Rahul Kushwah, Neil B Sweezey + Show 1 more

Open Access

https://doi.org/10.1186/1465-9921-14-138

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Abstract

BackgroundCystic fibrosis (CF) is a complex, multi-system, life-shortening, autosomal recessive disease most common among Caucasians. Pulmonary pathology, the major cause of morbidity and mortality in CF, is characterized by dysregulation of cytokines and a vicious cycle of infection and inflammation. This cycle causes a progressive decline in lung function, eventually resulting in respiratory failure and death. The Th17 immune response plays an active role in the pathogenesis of CF pulmonary pathology, but it is not known whether the pathophysiology of CF disease contributes to a heightened Th17 response or whether CF naïve CD4+ T lymphocytes (Th0 cells) intrinsically have a heightened predisposition to Th17 differentiation.MethodsTo address this question, Th0 cells were isolated from the peripheral blood of CF mice, human CF subjects and corresponding controls. Murine Th0 cells were isolated from single spleen cell suspensions using fluorescence-activated cell sorting. Lymphocytes from human buffy coats were isolated by gradient centrifugation and Th0 cells were further isolated using a human naïve T cell isolation kit. Th0 cells were then assessed for their capacity to differentiate along Th17, Th1 or Treg lineages in response to corresponding cytokine stimulation. The T cell responses of human peripheral blood cells were also assessed ex vivo using flow cytometry.ResultsHere we identify in both mouse and human CF an intrinsically enhanced predisposition of Th0 cells to differentiate towards a Th17 phenotype, while having a normal propensity for differentiation into Th1 and Treg lineages. Furthermore, we identify an active Th17 response in the peripheral blood of human CF subjects.ConclusionsWe propose that these novel observations offer an explanation, at least in part, for the known increased Th17-associated inflammation of CF and the early signs of inflammation in CF lungs before any evidence of infection. Moreover, these findings point towards direct modulation of T cell responses as a novel potential therapeutic strategy for combating excessive inflammation in CF.

Highlights

Cystic fibrosis (CF) is a complex, multi-system, life-shortening, autosomal recessive disease most common among Caucasians
Naïve CF transmembrane conductance regulator (CFTR)-/- CD4+ T cells preferentially undergo Th17 differentiation Initially, CFTR expression was thought to be restricted to epithelial cells [22,23], but later studies confirmed that CFTR is expressed in lymphocytes [4]
When cells were differentiated along the IL-17-producing Th17 lineage [21], 16% of naïve T cells from CFTR+/+ mice differentiated into IL-17 producing cells, whereas Th17 differentiation of naïve CFTR -/- T cells was almost 2 fold higher with approximately 25-30% cells undergoing differentiation into IL-17-producing cells (Figure 1H, I)

Summary

Introduction

Cystic fibrosis (CF) is a complex, multi-system, life-shortening, autosomal recessive disease most common among Caucasians. The major cause of morbidity and mortality in CF, is characterized by dysregulation of cytokines and a vicious cycle of infection and inflammation. This cycle causes a progressive decline in lung function, eventually resulting in respiratory failure and death. Studies have identified an active role of Th17 response in modulating CF pulmonary pathology, the underlying mechanism(s) promoting a Th17 response are not understood It is not known whether the pathophysiology of CF disease contributes to a heightened Th17 response, or whether naïve CF T cells are intrinsically prone to Th17 differentiation

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