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@article{Guvenel:2020:10.1172/JCI131696,
author = {Guvenel, A and Jozwik, A and Ascough, S and Ung, SK and Paterson, S and Kalyan, M and Bergstrom, E and Kar, S and Habibi, MS and Paras, A and Zhu, J and Park, M and Dhariwal, J and Almond, M and Wong, EHC and Sykes, A and Del, Rosario J and Trujillo-Torralbo, M and Mallia, P and Sidney, J and Peters, B and Kon, OM and Sette, A and Johnston, SL and Openshaw, PJ and Chiu, C},
doi = {10.1172/JCI131696},
journal = {Journal of Clinical Investigation},
pages = {523--538},
title = {Epitope-specific airway-resident CD4+ T-cell dynamics during experimental human RSV infection},
url = {http://dx.doi.org/10.1172/JCI131696},
volume = {130},
year = {2020}
}

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TY  - JOUR
AB  - 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-DPA101:03/DPB102:01   and   -DPA101:03/DPB104:01   (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.
AU  - Guvenel,A
AU  - Jozwik,A
AU  - Ascough,S
AU  - Ung,SK
AU  - Paterson,S
AU  - Kalyan,M
AU  - Bergstrom,E
AU  - Kar,S
AU  - Habibi,MS
AU  - Paras,A
AU  - Zhu,J
AU  - Park,M
AU  - Dhariwal,J
AU  - Almond,M
AU  - Wong,EHC
AU  - Sykes,A
AU  - Del,Rosario J
AU  - Trujillo-Torralbo,M
AU  - Mallia,P
AU  - Sidney,J
AU  - Peters,B
AU  - Kon,OM
AU  - Sette,A
AU  - Johnston,SL
AU  - Openshaw,PJ
AU  - Chiu,C
DO  - 10.1172/JCI131696
EP  - 538
PY  - 2020///
SN  - 0021-9738
SP  - 523
TI  - Epitope-specific airway-resident CD4+ T-cell dynamics during experimental human RSV infection
T2  - Journal of Clinical Investigation
UR  - http://dx.doi.org/10.1172/JCI131696
UR  - https://www.jci.org/articles/view/131696
UR  - http://hdl.handle.net/10044/1/75119
VL  - 130
ER  -

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