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

Abstract

BACKGROUNDRespiratory 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.METHODSHealthy 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.RESULTSActivated 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.CONCLUSIONSHuman 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 REGISTRATIONClinicalTrials.gov NCT02755948.FUNDINGMedical Research Council, Wellcome Trust, National Institute for Health Research.

T cell immunity to SARS-CoV-2 following natural infection and vaccination

“…Furthermore, airway CD4 + T cell-derived IFN-γ was required for optimal respiratory DC maturation and migration to the draining mediastinal lymph node. Finally, airway CD4 + T cell derived IFN-γ promoted CXCR3-dependent T cell mobilization to the lungs [ 17 ], consistent with models described for other viruses and sites of infection [ [18] , [19] , [20] ]. Taken together, murine studies of pathogenic coronavirus infection largely demonstrate a protective role for T cells and suggest that SARS-CoV-2-specific CD4 + and CD8 + T cells will control virus replication and moderate the pathology associated with COVID-19.…”

Conserved T-cell epitopes of respiratory syncytial virus (RSV) delivered by recombinant live attenuated influenza vaccine viruses efficiently induce RSV-specific lung-localized memory T cells and augment influenza-specific resident memory T-cell responses

“…RSV human challenge models will help to accelerate this vaccine development (Habibi and Chiu, 2017). In particular, new data are emerging regarding RSV epitopes for CD4 airway-resident T cells (Guvenel et al, 2020) and CD8 resident memory T cells (Jozwik et al, 2015) with a defined immunodominance hierarchy. In addition, a combination of B-cell and T-cell RSV epitopes can be considered for RSV vaccine design (Retamal-Diaz et al, 2019).…”

T Cell Immunity against Influenza: The Long Way from Animal Models Towards a Real-Life Universal Flu Vaccine

“…However, the investigation of human TRMs is difficult, since most immunological methods used in preclinical research are not applicable to humans. Thus, so far no direct investigation of TRM-mediated protection against flu infections has been conducted, but some insights could be generated in BAL samples, lung tissue biopsies [ 85 , 86 , 88 , 90 ], and human cadavers [ 74 , 87 ], as well as in the context of lung transplantation [ 123 ]. These studies have shown that CD4 + and CD8 + TRMs in the airways and lungs express CD69 and less stringently CD103.…”

“…Donor TRM populations persisted for more than 15 months after lung transplantation, and expressed canonical TRM markers like CD69, CD103, CD49a, and PD-1. Two studies from Christopher Chiu’s lab investigated CD8 + and CD4 + TRM responses in experimental human respiratory syncytial virus (RSV) infection [ 85 , 90 ]. Immune responses were assessed longitudinally in BAL samples showing an accumulation of CD69 + CD103 + TRM cells in the airways after convalescence.…”

“…Sampling of nasal tissue in clinical trials would be much less elaborate compared to sampling of the lung tissue. However, human challenge studies with RSV as well as studies from the Farber lab illustrate the feasibility of assessing CD4 + and CD8 + TRM responses in the lower respiratory tract by bronchial biopsies and BALs in humans [ 85 , 89 , 90 ]. An interesting alternative induction and sampling site for mucosal immunity are nasopharynx-associated lymphoid tissues, which include the adenoids and tonsils.…”