Epitope-specific airway-resident CD4⁺ T cell dynamics during experimental human RSV infection

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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 i.n. with RSV A Memphis 37. CD4+ T cells in blood and the lower airway were analyzed 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 C-X-C motif chemokine 10 levels. Thirty-nine epitopes were identified, predominantly toward the 3′ end of the viral genome. Five novel MHC II tetramers were made using an immunodominant EFYQSTCSAVSKGYL (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 labeling revealed enrichment of resident memory CD4+ T (Trm) cells in the lower airway; these Trm cells displayed progressive differentiation, downregulation of costimulatory molecules, and elevated CXCR3 expression as infection evolved.CONCLUSIONS 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 recognizing 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.TRIAL REGISTRATION ClinicalTrials.gov NCT02755948.FUNDING Medical Research Council, Wellcome Trust, National Institute for Health Research.

Authors

Aleks Guvenel, Agnieszka Jozwik, Stephanie Ascough, Seng Kuong Ung, Suzanna Paterson, Mohini Kalyan, Zoe Gardener, Emma Bergstrom, Satwik Kar, Maximillian S. Habibi, Allan Paras, Jie Zhu, Mirae Park, Jaideep Dhariwal, Mark Almond, Ernie H.C. Wong, Annemarie Sykes, Jerico Del Rosario, Maria-Belen Trujillo-Torralbo, Patrick Mallia, John Sidney, Bjoern Peters, Onn Min Kon, Alessandro Sette, Sebastian L. Johnston, Peter J. Openshaw, Christopher Chiu