Rapid Evolution of the CD8(+) TCR Repertoire in Neonatal Mice

AJ Carey, DT Gracias, JL Thayer, AC Boesteanu, OK Kumova, Yvonne Müller, Jennifer Hope, JA Fraietta, DBH van Zessen, Peter Katsikis

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17 Citations (Scopus)

Abstract

Currently, there is little consensus regarding the most appropriate animal model to study acute infection and the virus-specific CD8(+) T cell (CTL) responses in neonates. TCRb high-throughput sequencing in naive CTL of differently aged neonatal mice was performed, which demonstrated differential V beta family gene usage. Using an acute influenza infection model, we examined the TCR repertoire of the CTL response in neonatal and adult mice infected with influenza type Avirus. Three-day-old mice mounted a greatly reduced primary NP(366-374)-specific CTL response when compared with 7-d-old and adult mice, whereas secondary CTL responses were normal. Analysis of NP(366-374)-specific CTL TCR repertoire revealed different V beta gene usage and greatly reduced public clonotypes in 3-d-old neonates. This could underlie the impaired CTL response in these neonates. To directly test this, we examined whether controlling the TCR would restore neonatal CTL responses. We performed adoptive transfers of both nontransgenic and TCR-transgenic OVA((257-264)-specific) (OT-I) CD8(+) T cells into influenza-infected hosts, which revealed that naive neonatal and adult OT-I cells expand equally well in neonatal and adult hosts. In contrast, nontransgenic neonatal CD8(+) T cells when transferred into adults failed to expand. We further demonstrate that differences in TCR avidity may contribute to decreased expansion of the endogenous neonatal CTL. These studies highlight the rapid evolution of the neonatal TCR repertoire during the first week of life and show that impaired neonatal CTL immunity results from an immature TCR repertoire, rather than intrinsic signaling defects or a suppressive environment.
Original languageUndefined/Unknown
Pages (from-to)2602-2613
Number of pages12
JournalJournal of Immunology
Volume196
Issue number6
DOIs
Publication statusPublished - 2016

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