RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection

Abstract

In animal models, resident memory CD8+ T (Trm) cells assist in respiratory virus elimination but their importance in man has not been determined. Here, using experimental human respiratory syncytial virus (RSV) infection, we investigate systemic and local virus-specific CD8+ T-cell responses in adult volunteers. Having defined the immunodominance hierarchy, we analyse phenotype and function longitudinally in blood and by serial bronchoscopy. Despite rapid clinical recovery, we note surprisingly extensive lower airway inflammation with persistent viral antigen and cellular infiltrates. Pulmonary virus-specific CD8+ T cells display a CD69+CD103+ Trm phenotype and accumulate to strikingly high frequencies into convalescence without continued proliferation. While these have a more highly differentiated phenotype, they express fewer cytotoxicity markers than in blood. Nevertheless, their abundance before infection correlates with reduced symptoms and viral load, implying that CD8+ Trm cells in the human lung can confer protection against severe respiratory viral disease when humoral immunity is overcome.

Controlled human infection with RSV: The opportunities of experimental challenge

“…Recently, these have been permitted on ethical review with assurances that they are carried out in clinical units with track records of safety and evidence of sufficient staffing and training. These have allowed direct access to respiratory mucosa, enabling sampling of local immune cells and epithelia, which is understood to be critical for further understanding of how to limit respiratory viral disease in man [17].…”

“…We recently investigated the role of virus-specific T cells in RSV infection in the experimental human infection model [17]. Using MHC-peptide tetramers, we labelled and tracked RSV-specific CD8+ T cells in blood and airways of experimentally infected volunteers, sampling the lower airway by bronchoscopy.…”

“…In the experimental human infection model, the frequency of RSV-specific CD8+ T cells in the airway (but not peripheral blood) prior to infection correlated with reduction in symptom severity and viral load on subsequent infection [17]. They were generated at extremely high frequencies during acute infection and continued to accumulate well into convalescence.…”

Vaccines in the Prevention of Viral Pneumonia

“…Although antibody induction is the major goal of vaccination against RSV disease, the recent demonstration that local mucosal CD8 T cells play a part in controlling viral load offers the prospect that T cell induction by vaccines might also be beneficial [87][88][89] .…”

Poly(U) and CpG ameliorate the unbalanced T cell immunity and pneumonia of mice with RSV vaccine-enhanced disease

“…Nonetheless, the deleterious impact of RSV infection on pediatric health is still difficult to avoid because no RSV vaccine has yet been authorized for clinical use (3). The development of RSV vaccine has been hampered by concerns about its safety and effectiveness, given that the first RSV vaccine clinical test in the 1960s showed that children previously inoculated with formalin-inactivated RSV vaccine (FIRSV) consequently suffered with enhanced respiratory disease after subsequent RSV exposure (4,5).…”