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



To investigate whether MAIT cells respond to NTHi and the effects of inhaled corticosteroids (ICS) on their frequency and function in COPD.



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.



Frequencies of Vα7.2+CD161+MAIT cells, surface expression of the major histocompatibility complex-related protein 1 (MR1), and intracellular IFN-γ expression were measured by flow cytometry. MAIT-cell frequencies were reduced in peripheral blood of ICS-treated 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-γ from CD4 cells and CD8 cells, but most potently from MAIT cells (median IFN-γ-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-γ secretion eightfold.



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.
1 Clinical & Experimental Sciences and.|2 Southampton NIHR Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton, United Kingdom.|3 Department for Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia; and.
Timothy S C
TS
Hinks
1 Clinical & Experimental Sciences and.
Joshua C
JC
Wallington
4 Cancer Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton, United Kingdom.|5 Wessex Investigational Sciences Hub, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom.
Anthony P
AP
Williams
1 Clinical & Experimental Sciences and.|2 Southampton NIHR Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton, United Kingdom.
Ratko
R
Djukanović
1 Clinical & Experimental Sciences and.|5 Wessex Investigational Sciences Hub, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom.
Karl J
0000-0003-3844-6457
KJ
Staples
1 Clinical & Experimental Sciences and.|2 Southampton NIHR Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton, United Kingdom.|5 Wessex Investigational Sciences Hub, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom.
Tom M A
TM
Wilkinson
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D005260:Female; D005434:Flow Cytometry; D006192:Haemophilus Infections / Q000150:complications / Q000276:immunology*; D006193:Haemophilus influenzae / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000072336:Mucosal-Associated Invariant T Cells / Q000187:drug effects* / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000276:immunology*; D055815:Young Adult
D000305:Adrenal Cortex Hormones
COPD; MAIT cell; NTHi; corticosteroids