Pulmonary Dendritic Cell Subsets Shape the Respiratory Syncytial Virus-Specific CD8+ T Cell Immunodominance Hierarchy...

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, K^dM2_82-90 and D^bM_187-195, 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 K^dM2_82-90 CD8⁺ 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 K^dM2_82-90 CD8⁺ 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.