tetano
Editor, Senior Moderator
Am J Respir Crit Care Med
. 2021 Jul 13.
doi: 10.1164/rccm.202103-0620OC. Online ahead of print.
Innate-like Gene Expression of Lung-resident Memory CD8+ T-cells During Experimental Human Influenza: A Clinical Study
Suzanna Paterson[SUP] 1 [/SUP], Satwik Kar[SUP] 1 [/SUP], Seng Kuong Ung[SUP] 1 [/SUP], Zoe Gardener[SUP] 1 [/SUP], Emma Bergstrom[SUP] 1 [/SUP], Stephanie Ascough[SUP] 2 [/SUP], Mohini Kalyan[SUP] 1 [/SUP], Joanna Zyla[SUP] 3 4 [/SUP], Jeroen Maertzdorf[SUP] 3 [/SUP], Hans-Joachim Mollenkopf[SUP] 3 [/SUP], January Weiner[SUP] 3 [/SUP], Agnieszka Jozwik[SUP] 5 [/SUP], Hannah Jarvis[SUP] 5 [/SUP], Akhilesh Jha[SUP] 6 [/SUP], Bradly P Nicholson[SUP] 7 [/SUP], Timothy Veldman[SUP] 8 [/SUP], Chris W Woods[SUP] 9 [/SUP], Patrick Mallia[SUP] 5 [/SUP], Onn Min Kon[SUP] 5 [/SUP], Stefan He Kaufmann[SUP] 3 [/SUP], Peter J Openshaw[SUP] 10 [/SUP], Christopher Chiu[SUP] 11 [/SUP]
Affiliations
Abstract
Rationale: Suboptimal vaccine immunogenicity and antigenic mismatch, compounded by poor uptake, means that influenza remains a major global disease. T-cells recognising 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-cells (Trm) 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(H1N1)2009. Blood, upper and (in a subgroup) lower airway samples were obtained throughout infection. Symptoms were assessed using self-reported diaries and nasal viral load by qPCR. T-cell responses were analysed by three-colour FluoroSpot, flow cytometry with MHC I-peptide tetramers and RNAseq, with candidate markers confirmed using immunohistochemistry of endobronchial biopsies.
Measurements and main results: Following challenge, 57% of participants became infected. Pre-existing influenza-specific CD8+ T-cells in blood correlated strongly with reduced viral load, which peaked at day 3. Influenza-specific CD8+ T-cells in BAL were highly enriched and predominantly expressed the Trm markers CD69 and CD103. Comparison between pre-infection CD8+ T-cells in BAL and blood by RNAseq revealed 3928 differentially expressed genes, including all major Trm cell markers. However, gene-set enrichment analysis of BAL 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 trial registration available at www.clinicaltrials.gov, ID: NCT02755948.
Keywords: Influenza, CD8+ T-cell, resident memory, controlled human infection.
. 2021 Jul 13.
doi: 10.1164/rccm.202103-0620OC. Online ahead of print.
Innate-like Gene Expression of Lung-resident Memory CD8+ T-cells During Experimental Human Influenza: A Clinical Study
Suzanna Paterson[SUP] 1 [/SUP], Satwik Kar[SUP] 1 [/SUP], Seng Kuong Ung[SUP] 1 [/SUP], Zoe Gardener[SUP] 1 [/SUP], Emma Bergstrom[SUP] 1 [/SUP], Stephanie Ascough[SUP] 2 [/SUP], Mohini Kalyan[SUP] 1 [/SUP], Joanna Zyla[SUP] 3 4 [/SUP], Jeroen Maertzdorf[SUP] 3 [/SUP], Hans-Joachim Mollenkopf[SUP] 3 [/SUP], January Weiner[SUP] 3 [/SUP], Agnieszka Jozwik[SUP] 5 [/SUP], Hannah Jarvis[SUP] 5 [/SUP], Akhilesh Jha[SUP] 6 [/SUP], Bradly P Nicholson[SUP] 7 [/SUP], Timothy Veldman[SUP] 8 [/SUP], Chris W Woods[SUP] 9 [/SUP], Patrick Mallia[SUP] 5 [/SUP], Onn Min Kon[SUP] 5 [/SUP], Stefan He Kaufmann[SUP] 3 [/SUP], Peter J Openshaw[SUP] 10 [/SUP], Christopher Chiu[SUP] 11 [/SUP]
Affiliations
- PMID: 34256007
- DOI: 10.1164/rccm.202103-0620OC
Abstract
Rationale: Suboptimal vaccine immunogenicity and antigenic mismatch, compounded by poor uptake, means that influenza remains a major global disease. T-cells recognising 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-cells (Trm) 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(H1N1)2009. Blood, upper and (in a subgroup) lower airway samples were obtained throughout infection. Symptoms were assessed using self-reported diaries and nasal viral load by qPCR. T-cell responses were analysed by three-colour FluoroSpot, flow cytometry with MHC I-peptide tetramers and RNAseq, with candidate markers confirmed using immunohistochemistry of endobronchial biopsies.
Measurements and main results: Following challenge, 57% of participants became infected. Pre-existing influenza-specific CD8+ T-cells in blood correlated strongly with reduced viral load, which peaked at day 3. Influenza-specific CD8+ T-cells in BAL were highly enriched and predominantly expressed the Trm markers CD69 and CD103. Comparison between pre-infection CD8+ T-cells in BAL and blood by RNAseq revealed 3928 differentially expressed genes, including all major Trm cell markers. However, gene-set enrichment analysis of BAL 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 trial registration available at www.clinicaltrials.gov, ID: NCT02755948.
Keywords: Influenza, CD8+ T-cell, resident memory, controlled human infection.