Impaired CD8+ T cell responses to influenza infection in neonatal mice are due to the immature T cell receptor repertoire (VIR2P.1020)

Abstract

Abstract To understand the role of virus antigen-specific CD8+ T cell responses in neonates during respiratory viral infection, we developed a model where 3-day old C57Bl/6 mice were infected intranasally with influenza type A virus strain A PR/8/34 (H1N1). When these neonatal mice are infected with influenza virus they mount a greatly reduced and delayed lung NP(366-374)-specific primary CD8+ T cell response. To investigate what was responsible for the reduced response, we performed adoptive transfers of TCR-transgenic OVA(257-264)-specific (OT-I) CD8+ T cells into hosts infected with recombinant influenza virus WSN-OVA, which expresses the OVA(257-264) peptide. These studies revealed that naïve adult OT-I cells expand equally well in neonatal and adult hosts, which excludes the neonatal environment as an inhibitor of the CD8+ T cell response. When naïve neonatal OT-I cells were transferred into neonatal and adult hosts, these neonatal OT-I cells expanded equally as well as adult OT-I cells, excluding an intrinsic defect in the neonatal CD8+ T cells. These studies demonstrate that the TCR repertoire of neonates is responsible for reduced CD8+ T cell immunity in neonates, not a suppressive environment or intrinsic signaling defects. Finally, despite impaired primary response, animals primed as neonates exhibited normal secondary responses to influenza virus. These findings raise important issues that need to be taken into consideration for vaccination of neonates.