Generic Portal

TY - JOUR

T1 - Allergic sensitization impairs lung resident memory CD8 T-cell response and virus clearance

AU - Agrawal, Komal

AU - Ong, Li Ching

AU - Monkley, Susan

AU - Thörn, Kristofer

AU - Israelsson, Elisabeth

AU - Baturcam, Engin

AU - Rist, Cassie

AU - Schön, Karin

AU - Blake, Sophia

AU - Magnusson, Björn

AU - Cartwright, James

AU - Mitra, Suman

AU - Ravi, Abilash

AU - U-BIOPRED study group

AU - Zounemat-Kermani, Nazanin

AU - Krishnaswamy, Jayendra Kumar

AU - Lycke, Nils Y.

AU - Gehrmann, Ulf

AU - Mattsson, Johan

N1 - Funding Information: This work was supported by AstraZeneca. The U-BIOPRED Consortium has received funding from the European Union and from the European Federation of Pharmaceutical Industries and Associations as an Innovative Medicines Initiative Joint Undertaking (under grant agreement no. 115010). Disclosure of potential conflict of interest: K. Agrawal, S. Monkley, K. Thörn, E. Israelsson, E. Baturcam, C. Rist, B. Magnusson, J. Cartwright, U. Gehrmann, and J. Mattsson are employees of AstraZeneca, which supported the study. J. K. Krishnaswamy is now an employee of Galderma SA and S. Blake is now an employee of Roche Diagnostics GmbH (these companies have not provided any funding or input toward this study). The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: This work was supported by AstraZeneca . The U-BIOPRED Consortium has received funding from the European Union and from the European Federation of Pharmaceutical Industries and Associations as an Innovative Medicines Initiative Joint Undertaking (under grant agreement no. 115010). Publisher Copyright: © 2022 American Academy of Allergy, Asthma & Immunology

PY - 2022/12

Y1 - 2022/12

N2 - Background: Patients with asthma often suffer from frequent respiratory viral infections and reduced virus clearance. Lung resident memory T cells provide rapid protection against viral reinfections. Objective: Because the development of resident memory T cells relies on the lung microenvironment, we investigated the impact of allergen sensitization on the development of virus-specific lung resident memory T cells and viral clearance. Methods: Mice were sensitized with house dust mite extract followed by priming with X47 and a subsequent secondary influenza infection. Antiviral memory T-cell response and protection to viral infection was assessed before and after secondary influenza infection, respectively. Gene set variation analysis was performed on data sets from the U-BIOPRED asthma cohort using an IFN-γ–induced epithelial cell signature and a tissue resident memory T-cell signature. Results: Viral loads were higher in lungs of sensitized compared with nonsensitized mice after secondary infection, indicating reduced virus clearance. X47 priming induced fewer antiviral lung resident memory CD8 T cells and resulted in lower pulmonary IFN-γ levels in the lungs of sensitized as compared with nonsensitized mice. Using data from the U-BIOPRED cohort, we found that patients with enrichment of epithelial IFN-γ–induced genes in nasal brushings and bronchial biopsies were also enriched in resident memory T-cell–associated genes, had more epithelial CD8 T cells, and reported significantly fewer exacerbations. Conclusions: The allergen-sensitized lung microenvironment interferes with the formation of antiviral resident memory CD8 T cells in lungs and virus clearance. Defective antiviral memory response might contribute to increased susceptibility of patients with asthma to viral exacerbations.

AB - Background: Patients with asthma often suffer from frequent respiratory viral infections and reduced virus clearance. Lung resident memory T cells provide rapid protection against viral reinfections. Objective: Because the development of resident memory T cells relies on the lung microenvironment, we investigated the impact of allergen sensitization on the development of virus-specific lung resident memory T cells and viral clearance. Methods: Mice were sensitized with house dust mite extract followed by priming with X47 and a subsequent secondary influenza infection. Antiviral memory T-cell response and protection to viral infection was assessed before and after secondary influenza infection, respectively. Gene set variation analysis was performed on data sets from the U-BIOPRED asthma cohort using an IFN-γ–induced epithelial cell signature and a tissue resident memory T-cell signature. Results: Viral loads were higher in lungs of sensitized compared with nonsensitized mice after secondary infection, indicating reduced virus clearance. X47 priming induced fewer antiviral lung resident memory CD8 T cells and resulted in lower pulmonary IFN-γ levels in the lungs of sensitized as compared with nonsensitized mice. Using data from the U-BIOPRED cohort, we found that patients with enrichment of epithelial IFN-γ–induced genes in nasal brushings and bronchial biopsies were also enriched in resident memory T-cell–associated genes, had more epithelial CD8 T cells, and reported significantly fewer exacerbations. Conclusions: The allergen-sensitized lung microenvironment interferes with the formation of antiviral resident memory CD8 T cells in lungs and virus clearance. Defective antiviral memory response might contribute to increased susceptibility of patients with asthma to viral exacerbations.

KW - Asthma

KW - IFN-γ

KW - exacerbations

KW - influenza infection

KW - mouse model

KW - tissue resident memory T (TRM) cells

UR - http://www.scopus.com/inward/record.url?scp=85136688714&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2022.07.004

DO - 10.1016/j.jaci.2022.07.004

M3 - Article

C2 - 35917932

VL - 150

SP - 1415-1426.e9

JO - Journal of allergy and clinical immunology

JF - Journal of allergy and clinical immunology

SN - 0091-6749

IS - 6

ER -