Innate-like Gene Expression of Lung-Resident Memory CD8(+) T Cells during Experimental Human Influenza: A Clinical Study
| Autor: | Christopher W. Woods, Zoe Gardener, Onn Min Kon, Agnieszka Jozwik, Peter J. M. Openshaw, Bradly P. Nicholson, Patrick Mallia, Satwik Kar, Suzanna Paterson, Jeroen Maertzdorf, Mohini Kalyan, Hans-Joachim Mollenkopf, Hannah Jarvis, January Weiner, Seng Kuong Ung, Akhilesh Jha, Stefan H. E. Kaufmann, Timothy Veldman, Joanna Zyla, Stephanie Ascough, Emma Bergstrom, Christopher Chiu |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Adult
Antigens Differentiation T-Lymphocyte Male Pulmonary and Respiratory Medicine Adolescent Human influenza Respiratory System Gene Expression Disease Adaptive Immunity CD8-Positive T-Lymphocytes Critical Care and Intensive Care Medicine Clinical study Young Adult Influenza A Virus H1N1 Subtype Antigen Vaccine Immunogenicity Orthomyxoviridae Infections Antigens CD Gene expression Influenza Human Medicine Cytotoxic T cell Humans Lectins C-Type Lung business.industry Gene Expression Profiling Editorials Original Articles Middle Aged Viral Load Healthy Volunteers Immunity Innate Kinetics Phenotype medicine.anatomical_structure Immunology Female Chemokines business Bronchoalveolar Lavage Fluid Integrin alpha Chains Biomarkers |
| Zdroj: | Am J Respir Crit Care Med American Journal of Respiratory and Critical Care Medicine |
| Popis: | 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 (NCT 02755948). |
| Databáze: | OpenAIRE |
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