Open AccessInnate-like Gene Expression of Lung-Resident Memory CD8+ T Cells during Experimental Human Influenza: A Clinical Study
Author(s) -
Suzanna Paterson,
Satwik Kar,
Seng Kuong Anakin Ung,
Zoe Gardener,
Emma Bergstrom,
Stephanie Ascough,
Mohini Kalyan,
Joanna Żyła,
Jeroen Maertzdorf,
Hans-Joachim Mollenkopf,
January Weiner,
Agnieszka Jóźwik,
Hannah Jarvis,
Akhilesh Jha,
Bradly P. Nicholson,
Timothy Veldman,
Chris W Woods,
Patrick Mallia,
Onn Min Kon,
Stefan H. E. Kaufmann,
Peter Openshaw,
Christopher Chiu
Publication year - 2021
Publication title -
american journal of respiratory and critical care medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.272
H-Index - 374
eISSN - 1535-4970
pISSN - 1073-449X
DOI - 10.1164/rccm.202103-0620oc
Subject(s) - immunology , cd8 , virology , influenza a virus , antigen , medicine , immunogenicity , virus , t cell , cytotoxic t cell , biology , immune system , in vitro , biochemistry
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 + 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 + T cells in blood correlated strongly with a reduced viral load, which peaked at Day 3. Influenza-specific CD8 + T cells in BAL fluid were highly enriched and predominantly expressed the Trm markers CD69 and CD103. Comparison between preinfection CD8 + 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 + 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 + cells in bronchial tissues. Conclusions: CD8 + 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).