title: Pulmonary Dendritic Cell Subsets Shape the Respiratory Syncytial Virus-Specific CD8+ T Cell Immunodominance Hierarchy in Neonates.
abstract: Young infants are generally more susceptible to viral infections and experience more severe disease than do adults. CD8+T cells are important for viral clearance, and although often ineffective in neonates they can be protective when adequately stimulated. Using a murine CB6F1/J hybrid model of respiratory syncytial virus (RSV) infection, we previously demonstrated that the CD8+T cell immunodominance hierarchy to two RSV-derived epitopes, KdM282-90and DbM187-195, was determined by the age at infection. To determine whether age-dependent RSV-specific CD8+T cell responses could be modified through enhanced innate signaling, we used TLR4 or TLR9 agonist treatment at the time of infection, which remarkably changed the neonatal codominant response to an adult-like KdM282-90CD8+T cell immunodominant response. This shift was associated with an increase in the number of conventional dendritic cells, CD11b+and CD103+dendritic cells, in the lung-draining lymph node, as well as increased expression of the costimulatory molecule CD86. The magnitude of the KdM282-90CD8+T cell response in TLR agonist-treated neonates could be blocked with Abs against CD80 and CD86. These studies demonstrate the age-dependent function of conventional dendritic cells, their role in determining immunodominance hierarchy, and epitope-specific CD8+T cell requirements for costimulation, all of which influence the immune response magnitude. The unique impact of TLR agonists on neonatal T cell responses is important to consider for RSV vaccines designed for young infants.
authors.affiliation: Laboratory of Neonatal Infection and Immunity, Department of Pediatrics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; and allison.malloy@usuhs.edu.|Viral Pathogenesis Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Allison M W
authors.identifier: 0000-0003-2962-0302
authors.initials: AM
authors.lastname: Malloy
authors.affiliation: Viral Pathogenesis Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Ruckwardt
authors.affiliation: Viral Pathogenesis Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Kaitlyn M
authors.initials: KM
authors.lastname: Morabito
authors.affiliation: Laboratory of Neonatal Infection and Immunity, Department of Pediatrics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; and.
authors.forename: Annie W
authors.identifier: 0000-0002-2666-1347
authors.initials: AW
authors.lastname: Lau-Kilby
authors.affiliation: Viral Pathogenesis Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Barney S
authors.initials: BS
authors.lastname: Graham
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016056:Immunodominant Epitopes / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000821:virology; D051379:Mice; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology*; D012136:Respiratory Syncytial Viruses
chemical_list: D016056:Immunodominant Epitopes