title: Rapid Evolution of the CD8+ TCR Repertoire in Neonatal Mice.
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. TCRβ high-throughput sequencing in naive CTL of differently aged neonatal mice was performed, which demonstrated differential Vβ 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 A virus. 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 Vβ 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.
authors.affiliation: Pediatrics, Drexel University College of Medicine, Philadelphia, PA 19102; Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102; alison.carey@drexelmed.edu p.katsikis@erasmusmc.nl.
authors.forename: Alison J
authors.identifier: http://orcid.org/0000-0001-7610-5659
authors.initials: AJ
authors.lastname: Carey
authors.affiliation: Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102;
authors.forename: Donald T
authors.identifier: http://orcid.org/0000-0002-3142-9059
authors.initials: DT
authors.lastname: Gracias
authors.affiliation: Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102;
authors.forename: Jillian L
authors.identifier: http://orcid.org/0000-0001-8635-0914
authors.initials: JL
authors.lastname: Thayer
authors.affiliation: Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102;
authors.forename: Alina C
authors.identifier: http://orcid.org/0000-0001-7176-1809
authors.initials: AC
authors.lastname: Boesteanu
authors.affiliation: Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102;
authors.forename: Ogan K
authors.identifier: http://orcid.org/0000-0001-8455-8850
authors.initials: OK
authors.lastname: Kumova
authors.affiliation: Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102; Immunology, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands;
authors.forename: Yvonne M
authors.identifier: http://orcid.org/0000-0002-4654-7509
authors.initials: YM
authors.lastname: Mueller
authors.affiliation: Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102; Immunology, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands;
authors.forename: Jennifer L
authors.identifier: http://orcid.org/0000-0002-2363-5442
authors.initials: JL
authors.lastname: Hope
authors.affiliation: Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Joseph A
authors.identifier: http://orcid.org/0000-0001-7900-8993
authors.initials: JA
authors.lastname: Fraietta
authors.affiliation: Immunology, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands; Bioinformatics, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands.
authors.forename: David B H
authors.initials: DB
authors.lastname: van Zessen
authors.affiliation: Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102; Immunology, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands; alison.carey@drexelmed.edu p.katsikis@erasmusmc.nl.
authors.forename: Peter D
authors.identifier: http://orcid.org/0000-0001-7690-5218
authors.initials: PD
authors.lastname: Katsikis
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000831:Animals, Newborn / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D004195:Disease Models, Animal; D005434:Flow Cytometry; D059014:High-Throughput Nucleotide Sequencing; D009980:Influenza A virus; D038041:Lymphopoiesis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta