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Innate-like Gene Expression of Lung-Resident Memory CD8 + T Cells during Experimental Human Influenza: A Clinical Study.

Authors :
Paterson S
Kar S
Ung SK
Gardener Z
Bergstrom E
Ascough S
Kalyan M
Zyla J
Maertzdorf J
Mollenkopf HJ
Weiner J
Jozwik A
Jarvis H
Jha A
Nicholson BP
Veldman T
Woods CW
Mallia P
Kon OM
Kaufmann SHE
Openshaw PJ
Chiu C
Source :
American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2021 Oct 01; Vol. 204 (7), pp. 826-841.
Publication Year :
2021

Abstract

Rationale: Suboptimal vaccine immunogenicity and antigenic mismatch, compounded by poor uptake, means that influenza remains a major global disease. T cells recognizing peptides derived from conserved viral proteins could enhance vaccine-induced cross-strain protection. Objectives: To investigate the kinetics, phenotypes, and function of influenza virus-specific CD8 <superscript>+</superscript> resident memory T (Trm) cells in the lower airway and infer the molecular pathways associated with their response to infection in vivo . Methods: Healthy volunteers, aged 18-55, were inoculated intranasally with influenza A/California/4/09(H1N1). Blood, upper airway, and (in a subgroup) lower airway samples were obtained throughout infection. Symptoms were assessed by using self-reported diaries, and the nasal viral load was assessed by using quantitative PCR. T-cell responses were analyzed by using a three-color FluoroSpot assay, flow cytometry with MHC I-peptide tetramers, and RNA sequencing, with candidate markers being confirmed by using the immunohistochemistry results for endobronchial biopsy specimens. Measurements and Main Results: After challenge, 57% of participants became infected. Preexisting influenza-specific CD8 <superscript>+</superscript> T cells in blood correlated strongly with a reduced viral load, which peaked at Day 3. Influenza-specific CD8 <superscript>+</superscript> T cells in BAL fluid were highly enriched and predominantly expressed the Trm markers CD69 and CD103. Comparison between preinfection CD8 <superscript>+</superscript> T cells in BAL fluid and blood by using RNA sequencing revealed 3,928 differentially expressed genes, including all major Trm-cell markers. However, gene set enrichment analysis of BAL-fluid CD8 <superscript>+</superscript> T cells showed primarily innate cell-related pathways and, during infection, included upregulation of innate chemokines ( Cxcl1 , Cxcl10 , and Cxcl16 ) that were also expressed by CD8 <superscript>+</superscript> cells in bronchial tissues. Conclusions: CD8 <superscript>+</superscript> Trm cells in the human lung display innate-like gene and protein expression that demonstrates blurred divisions between innate and adaptive immunity. Clinical study registered with www.clinicaltrials.gov (NCT02755948).

Details

Language :
English
ISSN :
1535-4970
Volume :
204
Issue :
7
Database :
MEDLINE
Journal :
American journal of respiratory and critical care medicine
Publication Type :
Academic Journal
Accession number :
34256007
Full Text :
https://doi.org/10.1164/rccm.202103-0620OC