Migration of regulatory T cells toward airway epithelial cells is impaired in chronic rhinosinusitis with nasal polyposis
Introduction
Chronic rhinosinusitis with nasal polyposis (CRSwNP) and without nasal polyposis (CRSsNP) are chronic and persistent inflammatory diseases of the nasal and paranasal sinus mucosa. CRSsNP is associated with a predominant TH1 polarization, whereas CRSwNP is typically characterized by TH2 skewed eosinophilic inflammation [1]. Although insights into the pathophysiology of CRS have largely expanded over the last two decades, further details on the etiology and pathogenesis need to be understood.
A number of recent studies indicate that CD4+CD25hiCD127lo/− regulatory T cells (Treg) play an important role in diseases characterized by TH2-biased immune responses such as asthma and atopic dermatitis [2], [3], [4]. Treg are chiefly involved in peripheral tolerance and are also important for normal immune homeostasis in the airway [5]. They can migrate to sites of inflammation and suppress immune responses via direct cell-cell contact, as well as secretion of TGF-β and IL-10 [6].
Forkhead box P3 (FOXP3) is specifically expressed by Treg and programs their development and function [7], [8]. Recent studies have reported a selective decrease in the frequency of regulatory T cells and expression of FOXP3 in nasal polyp tissue of CRSwNP patients compared with CRSsNP and control subjects [9], [10]. However, these studies did not clarify the reason for the impaired recruitment of these cells and the decreased expression of FOXP3 in the nasal polyps. A recent study demonstrated that a decreased number of Treg in bronchoalveolar lavage fluid (BALF) correlated with decreased migratory function of Treg in allergic asthma patients [11].
Treg express multiple chemokine receptors, controlling their migration to different organs and tissues [12]. Previous reports have shown that Treg express high levels of CCR4 and CCR8 and functionally respond to CCL17/CCL22 and CCL1, respectively [13], [14]. In allergic asthma, Treg showed decreased chemotactic responses, specifically to CCL1, in comparison with healthy controls [15]. Moreover, CCL1 was localized predominantly to the airway epithelium and may play a role in lymphocyte recruitment in bronchial asthma [16]. These studies indicated that several chemokines that are produced by airway epithelial cells can allow Treg to migrate into the tissue. Our preliminary data showed that airway epithelial cells produce chemokines for helper T cells, such as TSLP, in the basal state (data not shown).
In this study, we hypothesized that recruitment of Treg and expression of FOXP3 may be decreased in the nasal polyps of CRSwNP subjects, and that these are associated with impaired migratory function of Treg in CRSwNP subjects. We investigated whether Treg from patients with CRSwNP migrated to bronchial epithelial cells (BECs) and primary nasal epithelial cells (PNECs) to a lesser degree than Treg from patients with CRSsNP or healthy controls. Furthermore, we compared the absolute numbers and phenotype of Treg in the circulation between the 3 groups. Our data suggest that the migratory potentials of Treg toward airway epithelial cells were lower in CRSwNP patients compared with CRSsNP or controls.
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Patients
Twenty-four patients with CRSwNP, twenty-two patients with CRSsNP, and eighteen control subjects were included in the study of circulating Treg count. There were 9 asthma and 11 allergic rhinitis (AR) patients in the CRSwNP group, 3 asthma and 5 AR patients in the CRSsNP group, and 3 asthma and 3 AR patients in the control group. Samples from the ethmoid mucosa, nasal septal mucosa, and ethmoidal polyps (if present) were used for immunohistochemistry and QT-PCR, and were collected from eight
Frequencies of Treg in the tissue were lower in subjects with CRSwNP
Immunohistochemical staining was performed to determine the presence of FOXP3+CD3+ cells in the tissue samples from the three groups. Single tissue sections were double stained with both CD3 and FOXP3. This was the most optimal method at the current time to detect T cells with a regulatory phenotype in tissues. FOXP3+CD3+ cells were higher in both control subjects (Fig. 2A) and CRSsNP patients (Fig. 2C) compared to CRSwNP patients (Fig. 2B). The average counts for FOXP3+CD3+ cells per high
Discussion
Our results are in contrast to a previous report, in which both CRSsNP and CRSwNP patients demonstrated impaired regulatory T cell function and enhanced TH1/TH2/TH17 responses compared to control subjects [21]. Despite the different results, both studies support the hypothesis that a defect in the function of regulatory T cell system plays an important role in the pathogenesis of CRSwNP.
In a recent study, the number of Treg was lower in the BALF but not in the peripheral blood of asthmatic
Acknowledgments
We thank the patients and their families. We also thank the Immunity, Transplantation and Infectious Disease Institute at Stanford University (Seed Grant, Dr. Nadeau, PI) and thank the Department of Otolaryngology at Stanford University School of Medicine (Dr. Hwang and Dr. Jackler).
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These authors contributed equally to this work.