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Dysregulation of anti-viral function of CD8+T cells in the COPD lung: role of the PD1/PDL1 axis

Dysregulation of anti-viral function of CD8+T cells in the COPD lung: role of the PD1/PDL1 axis
Dysregulation of anti-viral function of CD8+T cells in the COPD lung: role of the PD1/PDL1 axis
Rationale: COPD patients are susceptible to respiratory viral infections which cause exacerbations. Mechanisms underlying susceptibility are not understood. Effectors of the adaptive immune response; CD8+ T cells which clear viral infections, are present in increased numbers in lungs of COPD patients but fail to protect against infection and may contribute to the immunopathology of the disease. Objectives: CD8+ function and signalling through the Programmed Cell Death (PD-1) exhaustion pathway was investigated as a potential key mechanism of viral exacerbation of the COPD lung. Methods: Tissue from control or COPD patients undergoing lung resection was infected with live influenza virus ex vivo. Viral infection and expression of lung cell markers was analysed using flow cytometry. Measurements and Main Results: The proportion of lung CD8+ T cells expressing PD-1 was greater in COPD(mean=16.2%) than controls(4.4%, p=0.029). Only epithelial cells and macrophages were infected with influenza and there was no difference in the proportion of infected cells between controls and COPD. Infection upregulated T cell PD-1 expression in control and COPD samples. Concurrently, influenza significantly upregulated the marker of cytotoxic degranulation (CD107a) on CD8+ T cells(p=0.03) from controls, but not from COPD patients. Virus-induced expression of the ligand PD-L1 was decreased on COPD macrophages(p=0.04) with a corresponding increase in IFN? release from infected COPD explants compared to controls(p=0.04). Conclusions: This study has established a signal of cytotoxic immune dysfunction and aberrant immune regulation in the COPD lung that may explain both the susceptibility to viral infection and the excessive, inflammation associated with exacerbations.
COPD, viral infection, T cell
1073-449X
1-56
McKendry, Richard T.
4450d027-46f7-4a87-aa8d-6079a6fe9171
Spalluto, C. Mirella
6802ad50-bc38-404f-9a19-40916425183b
Burke, Hannah
a9bb9391-4704-4584-aeb7-e69fe0acbdb8
Nicholas, Ben
785c44fb-6536-4189-803b-4545425e9385
Cellura, Doriana
e4cffc4c-0e12-40e7-ad13-e90e3fb55332
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Staples, Karl J.
e0e9d80f-0aed-435f-bd75-0c8818491fee
Wilkinson, Tom M.A.
8c55ebbb-e547-445c-95a1-c8bed02dd652
McKendry, Richard T.
4450d027-46f7-4a87-aa8d-6079a6fe9171
Spalluto, C. Mirella
6802ad50-bc38-404f-9a19-40916425183b
Burke, Hannah
a9bb9391-4704-4584-aeb7-e69fe0acbdb8
Nicholas, Ben
785c44fb-6536-4189-803b-4545425e9385
Cellura, Doriana
e4cffc4c-0e12-40e7-ad13-e90e3fb55332
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Staples, Karl J.
e0e9d80f-0aed-435f-bd75-0c8818491fee
Wilkinson, Tom M.A.
8c55ebbb-e547-445c-95a1-c8bed02dd652

McKendry, Richard T., Spalluto, C. Mirella, Burke, Hannah, Nicholas, Ben, Cellura, Doriana, Al-Shamkhani, Aymen, Staples, Karl J. and Wilkinson, Tom M.A. (2016) Dysregulation of anti-viral function of CD8+T cells in the COPD lung: role of the PD1/PDL1 axis. American Journal of Respiratory and Critical Care Medicine, 1-56. (doi:10.1164/rccm.201504-0782OC). (PMID:26517304)

Record type: Article

Abstract

Rationale: COPD patients are susceptible to respiratory viral infections which cause exacerbations. Mechanisms underlying susceptibility are not understood. Effectors of the adaptive immune response; CD8+ T cells which clear viral infections, are present in increased numbers in lungs of COPD patients but fail to protect against infection and may contribute to the immunopathology of the disease. Objectives: CD8+ function and signalling through the Programmed Cell Death (PD-1) exhaustion pathway was investigated as a potential key mechanism of viral exacerbation of the COPD lung. Methods: Tissue from control or COPD patients undergoing lung resection was infected with live influenza virus ex vivo. Viral infection and expression of lung cell markers was analysed using flow cytometry. Measurements and Main Results: The proportion of lung CD8+ T cells expressing PD-1 was greater in COPD(mean=16.2%) than controls(4.4%, p=0.029). Only epithelial cells and macrophages were infected with influenza and there was no difference in the proportion of infected cells between controls and COPD. Infection upregulated T cell PD-1 expression in control and COPD samples. Concurrently, influenza significantly upregulated the marker of cytotoxic degranulation (CD107a) on CD8+ T cells(p=0.03) from controls, but not from COPD patients. Virus-induced expression of the ligand PD-L1 was decreased on COPD macrophages(p=0.04) with a corresponding increase in IFN? release from infected COPD explants compared to controls(p=0.04). Conclusions: This study has established a signal of cytotoxic immune dysfunction and aberrant immune regulation in the COPD lung that may explain both the susceptibility to viral infection and the excessive, inflammation associated with exacerbations.

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McKendry et al 2015 Accepted Published online.pdf - Accepted Manuscript
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More information

Accepted/In Press date: 30 October 2015
e-pub ahead of print date: 30 October 2015
Published date: 15 March 2016
Keywords: COPD, viral infection, T cell
Organisations: Human Development & Health, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 383528
URI: https://eprints.soton.ac.uk/id/eprint/383528
ISSN: 1073-449X
PURE UUID: 1ca0fcfa-2fb7-41b8-b61b-ab3655731f2a
ORCID for Aymen Al-Shamkhani: ORCID iD orcid.org/0000-0003-0727-4189
ORCID for Karl J. Staples: ORCID iD orcid.org/0000-0003-3844-6457

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Date deposited: 02 Nov 2015 12:15
Last modified: 10 Dec 2019 01:51

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