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Steroid-induced deficiency of mucosal-associated invariant T cells in the COPD lung: implications for NTHi infection

Steroid-induced deficiency of mucosal-associated invariant T cells in the COPD lung: implications for NTHi infection
Steroid-induced deficiency of mucosal-associated invariant T cells in the COPD lung: implications for NTHi infection
Rationale: Mucosal associated invariant T (MAIT) cells are a recently-described, abundant, pro-inflammatory T cell subset with unknown roles in pulmonary immunity. Non-typeable Haemophilus influenzae (NTHi) is the leading bacterial pathogen during COPD exacerbations and a plausible target for MAIT cells.

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

Methods: 11 participants with COPD receiving inhaled corticosteroids (ICS), 8 with steroid-naïve COPD and 21 healthy controls underwent phlebotomy, sputum induction, bronchoalveolar-lavage and endobronchial biopsy. Pulmonary and monocyte-derived macrophages were cultured in vitro with NTHi.

Measurements: Frequencies of Va7.2+CD161+ MAIT cells, surface expression of MHC-related protein 1 (MR1) and intracellular IFN-y expression were measured by flow cytometry.

Main Results: MAIT cell frequencies were reduced in peripheral blood in ICS-treated COPD (median 0.38% (IQR, 0.25-0.96) compared with health (1.8% (IQR, 1.4-2.5), P=0.001)) or steroid-naïve COPD (1.8% (1.2-2.3), P=0.04). MAIT cells were reduced in bronchial biopsies in steroid-treated COPD (0.73% (0.46-1.3)) compared with health (4.0% (1.6-5.0), P=0.02). Co-culture of live NTHi increased macrophage surface expression of MR1 and induced IFN-? from CD4 cells and CD8 cells, but most potently from MAIT cells (median IFN-y positive frequencies 2.9%, 8.6% and 27.6% respectively). In vitro fluticasone and budesonide reduced MR1 surface expression 2-fold and decreased NTHi-induced IFN-y secretion 8-fold.

Conclusions: MAIT cells are deficient in blood and bronchial tissue in steroid-treated, but not steroid-naïve COPD. NTHi constitutes a target for pulmonary MAIT cell immune responses, which are significantly impaired by corticosteroids.
1073-449X
1-63
Hinks, Timothy
97bf168b-fd21-4e42-a4cf-34f85abe9e74
Wallington, Joshua
7f2909e0-96f1-4237-b2c2-ea3aa695a9d1
Williams, Anthony
973ff46f-46f1-4d7c-b27d-0f53221e4c44
Djukanovic, Ratko
d9a45ee7-6a80-4d84-a0ed-10962660a98d
Staples, Karl J
e0e9d80f-0aed-435f-bd75-0c8818491fee
Wilkinson, Thomas
8c55ebbb-e547-445c-95a1-c8bed02dd652
Hinks, Timothy
97bf168b-fd21-4e42-a4cf-34f85abe9e74
Wallington, Joshua
7f2909e0-96f1-4237-b2c2-ea3aa695a9d1
Williams, Anthony
973ff46f-46f1-4d7c-b27d-0f53221e4c44
Djukanovic, Ratko
d9a45ee7-6a80-4d84-a0ed-10962660a98d
Staples, Karl J
e0e9d80f-0aed-435f-bd75-0c8818491fee
Wilkinson, Thomas
8c55ebbb-e547-445c-95a1-c8bed02dd652

Hinks, Timothy, Wallington, Joshua, Williams, Anthony, Djukanovic, Ratko, Staples, Karl J and Wilkinson, Thomas (2016) Steroid-induced deficiency of mucosal-associated invariant T cells in the COPD lung: implications for NTHi infection. American Journal of Respiratory and Critical Care Medicine, 1-63. (doi:10.1164/rccm.201601-0002OC). (PMID:27115408)

Record type: Article

Abstract

Rationale: Mucosal associated invariant T (MAIT) cells are a recently-described, abundant, pro-inflammatory T cell subset with unknown roles in pulmonary immunity. Non-typeable Haemophilus influenzae (NTHi) is the leading bacterial pathogen during COPD exacerbations and a plausible target for MAIT cells.

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

Methods: 11 participants with COPD receiving inhaled corticosteroids (ICS), 8 with steroid-naïve COPD and 21 healthy controls underwent phlebotomy, sputum induction, bronchoalveolar-lavage and endobronchial biopsy. Pulmonary and monocyte-derived macrophages were cultured in vitro with NTHi.

Measurements: Frequencies of Va7.2+CD161+ MAIT cells, surface expression of MHC-related protein 1 (MR1) and intracellular IFN-y expression were measured by flow cytometry.

Main Results: MAIT cell frequencies were reduced in peripheral blood in ICS-treated COPD (median 0.38% (IQR, 0.25-0.96) compared with health (1.8% (IQR, 1.4-2.5), P=0.001)) or steroid-naïve COPD (1.8% (1.2-2.3), P=0.04). MAIT cells were reduced in bronchial biopsies in steroid-treated COPD (0.73% (0.46-1.3)) compared with health (4.0% (1.6-5.0), P=0.02). Co-culture of live NTHi increased macrophage surface expression of MR1 and induced IFN-? from CD4 cells and CD8 cells, but most potently from MAIT cells (median IFN-y positive frequencies 2.9%, 8.6% and 27.6% respectively). In vitro fluticasone and budesonide reduced MR1 surface expression 2-fold and decreased NTHi-induced IFN-y secretion 8-fold.

Conclusions: MAIT cells are deficient in blood and bronchial tissue in steroid-treated, but not steroid-naïve COPD. NTHi constitutes a target for pulmonary MAIT cell immune responses, which are significantly impaired by corticosteroids.

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Accepted/In Press date: 25 April 2016
e-pub ahead of print date: 26 April 2016
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 393511
URI: https://eprints.soton.ac.uk/id/eprint/393511
ISSN: 1073-449X
PURE UUID: eacb3482-8f50-4daa-893d-3b5435ca6c14
ORCID for Ratko Djukanovic: ORCID iD orcid.org/0000-0001-6039-5612
ORCID for Karl J Staples: ORCID iD orcid.org/0000-0003-3844-6457

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Date deposited: 27 Apr 2016 11:18
Last modified: 10 Dec 2019 06:33

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