Epitope-specific airway-resident CD4+ T-cell dynamics during experimental human RSV infection
File(s)
Author(s)
Type
Journal Article
Abstract
Background: Respiratory syncytial virus (RSV) is an important cause of acute pulmonary disease and one of the last remaining major infections of childhood for which there is no vaccine. CD4+ T-cells play a key role in antiviral immunity, but they have been little studied in the human lung. Methods: Healthy adult volunteers were inoculated intranasally with RSV A Memphis 37. CD4+ T-cells in blood and lower airway were analysed by flow cytometry and immunohistochemistry. Bronchial soluble mediators were measured using quantitative PCR and MesoScale Discovery. Epitope mapping was performed by IFN-γ ELISpot screening, confirmed by in vitro MHC binding. Results: Activated CD4+ T-cell frequencies in bronchoalveolar lavage correlated strongly with local CXCL10 levels. Thirty-nine epitopes were identified, predominantly towards the 3’ end of the viral genome. Five novel MHC-II tetramers were made using an immunodominant F-EFY epitope restricted to HLA-DR4, -DR9 and -DR11 (combined allelic frequency: 15% in Europeans) and G- DDF restricted to HLA-DPA1*01:03/DPB1*02:01 and -DPA1*01:03/DPB1*04:01 (allelic frequency: 55%). Tetramer labelling revealed enrichment of resident memory CD4+ T-cells (TRM) cells in the lower airway; these TRM displayed progressive differentiation, down-regulation of co- stimulatory molecules and elevated CXCR3 expression as infection evolved. Conclusion: Human infection challenge provides a unique opportunity to study the breadth of specificity and dynamics of RSV-specific T-cell responses in the target organ, allowing the precise investigation of TRM recognising novel viral antigens over time. The new tools that we describe enable precise tracking of RSV-specific CD4+ cells, potentially accelerating the development of effective vaccines.
Date Issued
2020-01-02
Date Acceptance
2019-10-08
Citation
Journal of Clinical Investigation, 2020, 130 (1), pp.523-538
ISSN
0021-9738
Publisher
American Society for Clinical Investigation
Start Page
523
End Page
538
Journal / Book Title
Journal of Clinical Investigation
Volume
130
Issue
1
Copyright Statement
© 2020, Guvenel et al. This is an open access article published under the
terms of the Creative Commons Attribution 4.0 International License.
terms of the Creative Commons Attribution 4.0 International License.
Sponsor
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
National Institute for Health Research
National Institute for Health Research
National Institute for Health Research
Asthma UK
Commission of the European Communities
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
GlaxoSmithKline Services Unlimited
National Institute for Health Research
Wellcome Trust
Identifier
https://www.jci.org/articles/view/131696
Grant Number
G0902266
MR/T50256X/1
MRC Ref G0400503
NF-SI-0513-10150
HPRU-2012-10064
RDA06 79560
Asthma UK Centre
116019
MR/R502121/1
MR/R005982/1
MR/R005982/1
PO 4050681719
PO 3000941762
RDF04
214407/Z/18/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
RESPIRATORY-SYNCYTIAL-VIRUS
IMMUNE-RESPONSE
F-PROTEIN
MEMORY
DISEASE
EXPRESSION
PROTECTION
IDENTIFICATION
INFLAMMATION
INHIBITION
Adaptive immunity
Immunology
Infectious disease
T cells
Immunology
11 Medical and Health Sciences
Publication Status
Published
Date Publish Online
2019-12-09