Steroid-induced Deficiency of Mucosal-associated Invariant T Cells in the Chronic Obstructive Pulmonary Disease Lung. Implications for Nontypeable Haemophilus influenzae Infection

Abstract

Rationale: Mucosal-associated invariant T (MAIT) cells are a recently described abundant, proinflammatory T-cell subset with unknown roles in pulmonary immunity. Nontypeable Haemophilus influenzae (NTHi) is the leading bacterial pathogen during chronic obstructive pulmonary disease (COPD) exacerbations and is a plausible target for MAIT cells.Objectives: To investigate whether MAIT cells respond to NTHi and the effects of inhaled corticosteroids (ICS) on their frequency and function in COPD.Methods: Eleven subjects with COPD receiving ICS, 8 steroid-naive subjects with COPD, and 21 healthy control subjects underwent phlebotomy, sputum induction, bronchoalveolar lavage, and endobronchial biopsy. Pulmonary and monocyte-derived macrophages were cultured in vitro with NTHi.Measurements and Main Results: Frequencies of Va7.2 1 CD161 1 MAIT cells, surface expression of the major histocompatibility complex-related protein 1 (MR1), and intracellular IFN-g expression were measured by flow cytometry. MAIT-cell frequencies were reduced in peripheral blood of ICStreated subjects with COPD (median 0.38%; interquartile range [IQR], 0.25-0.96) compared with healthy control subjects (1.8%; IQR, 1.4-2.5; P = 0.001) or steroid-naive patients with COPD (1.8%; IQR, 1.2-2.3; P = 0.04). MAIT cells were reduced in bronchial biopsies from subjects with COPD treated with steroids (0.73%; IQR, 0.46-1.3) compared with healthy control subjects (4.0%; IQR, 1.6-5.0; P = 0.02). Coculture of live NTHi increased macrophage surface expression of MR1 and induced IFN-g from CD4 cells and CD8 cells, but most potently from MAIT cells (median IFN-g-positive frequencies, 2.9, 8.6, and 27.6%, respectively). In vitro fluticasone and budesonide reduced MR1 surface expression twofold and decreased NTHi-induced IFN-g secretion eightfold.Conclusions: MAIT cells are deficient in blood and bronchial tissue in steroid-treated, but not steroid-naive, COPD. NTHi constitutes a target for pulmonary MAIT-cell immune responses, which are significantly impaired by corticosteroids.

Innate Immunity of the Lung: From Basic Mechanisms to Translational Medicine

“…MAIT are a group of innate-like T lymphocytes that which are highly abundant in human blood (~1–10% [100]) and in mucosal tissues such as the intestine and lungs [101–104]. These cells are characterized by their expression of the invariant T-cell receptor (TCR) α chain, TRAV1–2 joined with TRAJ33 and a limited range of TCRβ chains, and abundant expression of CD161 and CD218 (IL18Rα) [102, 105, 106].…”

“…The frequency of MAIT cells in normal human lungs ranges from 2 to 20% of all T cells [104, 117]. Given their abundance in blood, many studies have examined blood MAIT cells in various respiratory diseases.…”

“…Given their abundance in blood, many studies have examined blood MAIT cells in various respiratory diseases. There were no change in MAIT cell frequency in the blood of inhaled corticosteroid (ICS)-naive COPD patients relative to healthy donors; however, their frequency was significantly reduced in ICS-treated COPD patients’ blood and bronchial biopsies [104]. The reduced MAIT cell frequency in blood was more pronounced in moderate-to-severe-COPD patients, and it was associated with elevated serum C-reactive protein levels and a reduced lung function [118].…”

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…Intrahepatic MAIT cells have been shown to be highly activated and express CD69, HLA‐DR and CD38, and are positioned around bile ducts within hepatic portal tracts 111, 118. Furthermore, as their name suggests, they are abundant within the gut, particularly in the jejunum and colon10, 119 through their expression of gut‐homing markers α 4 β 7 and CCR9,11, 13, 118 as well as the lungs 120…”

Lung Microbiota and Its Impact on the Mucosal Immune Phenotype

“…Although they are able to recognize a wide variety of bacteria microorganisms, bacteria that do not express riboflavin synthesis pathways do not stimulate MAIT cells(114). Hinks and colleagues demonstrated that in 11 patients who were exposed to inhaled corticosteroids, peripheral serum and bronchial biopsies contained less MAIT cells compared to healthy controls(115). In in vitro studies, non-typeable Haemophilus influenzae (NTHi) infection of macrophages obtained from healthy subjects were exposed to fluticasone or budesonide.…”