title: The Neonatal CD8+ T Cell Repertoire Rapidly Diversifies during Persistent Viral Infection.
abstract: CMV is the most common congenital infection in the United States. The major target of congenital CMV is the brain, with clinical manifestations including mental retardation, vision impairment, and sensorineural hearing loss. Previous reports have shown that CD8(+) T cells are required to control viral replication and significant numbers of CMV-specific CD8(+) T cells persist in the brain even after the initial infection has been cleared. However, the dynamics of CD8(+) T cells in the brain during latency remain largely undefined. In this report, we used TCR sequencing to track the development and maintenance of neonatal clonotypes in the brain and spleen of mice during chronic infection. Given the discontinuous nature of tissue-resident memory CD8(+) T cells, we hypothesized that neonatal TCR clonotypes would be locked in the brain and persist into adulthood. Surprisingly, we found that the Ag-specific T cell repertoire in neonatal-infected mice diversified during persistent infection in both the brain and spleen, while maintaining substantial similarity between the CD8(+) T cell populations in the brain and spleen in both early and late infection. However, despite the diversification of, and potential interchange between, the spleen and brain Ag-specific T cell repertoires, we observed that germline-encoded TCR clonotypes, characteristic of neonatal infection, persisted in the brain, albeit sometimes in low abundance. These results provide valuable insights into the evolution of CD8(+) T cell repertoires following neonatal CMV infection and thus have important implications for the development of therapeutic strategies to control CMV in early life.
authors.affiliation: Kirby Institute for Infection and Immunity, University of New South Wales Australia, Sydney, New South Wales 2052, Australia; v.venturi@unsw.edu.au m.davenport@unsw.edu.au bdr54@cornell.edu.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Venturi
authors.affiliation: Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14850;
authors.forename: Kito
authors.initials: K
authors.lastname: Nzingha
authors.affiliation: Kirby Institute for Infection and Immunity, University of New South Wales Australia, Sydney, New South Wales 2052, Australia;
authors.forename: Timothy G
authors.identifier: http://orcid.org/0000-0002-5829-6655
authors.initials: TG
authors.lastname: Amos
authors.affiliation: Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14850;
authors.forename: Wisler C
authors.identifier: http://orcid.org/0000-0002-1988-7196
authors.initials: WC
authors.lastname: Charles
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; and.
authors.forename: Iryna
authors.initials: I
authors.lastname: Dekhtiarenko
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; and Institute for Virology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Luka
authors.initials: L
authors.lastname: Cicin-Sain
authors.affiliation: Kirby Institute for Infection and Immunity, University of New South Wales Australia, Sydney, New South Wales 2052, Australia; v.venturi@unsw.edu.au m.davenport@unsw.edu.au bdr54@cornell.edu.
authors.forename: Miles P
authors.identifier: http://orcid.org/0000-0002-4751-1831
authors.initials: MP
authors.lastname: Davenport
authors.affiliation: Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14850; v.venturi@unsw.edu.au m.davenport@unsw.edu.au bdr54@cornell.edu.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Rudd
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology*; D019672:Genes, T-Cell Receptor; D007156:Immunologic Memory; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta