Evolution of the antigen-specific CD8+ TCR repertoire across the life span: evidence for clonal homogenization of the old TCR repertoire.
Defects in T cell responses against pathogens and reduced diversity of TCRs have been described at both extremes of the life span. Yet, we still lack information on how Ag-specific T cell populations are maintained and/or altered from birth to old age. In this study, for the first time to our knowledge, we provide insight into Ag-specific TCR repertoire changes over the life span at the single-cell level. We have examined the TCR diversity of the primary CD8(+) T cell response to the immunodominant HSV-1 epitope HSV glycoprotein B 495-502 (HSV gB(498-505); SSIEFARL) (gB-8p) in neonatal, adult, and old C57BL/6 mice. The global distinctive features of the gB-8p-specific TCR repertoire were preserved in mice of different ages. However, both old and especially neonatal mice exhibited significant decreases in TCR diversity compared with that of adult mice. Still, although the neonatal Ag-specific repertoire comprised expectedly shorter germline-biased CDR3β lengths, the repertoire was surprisingly complex, and only a minority of responding cells lacked random nucleotide additions. Changes with aging included increased use of the already dominant TCRVβ10 family, a trend for lower content of the TCR containing the germline WG motif in the CDR3, and a remarkable sharing of one dominant clonotype between individual old mice, implying operation of selective mechanisms. Implications for the rational design of vaccines for neonates and the elderly are discussed.
Department of Immunobiology and, the Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85724 and the BIO-5 Institute, University of Arizona, Tucson ,AZ 85719.
Brian D
BD
Rudd
Computational Biology Unit, University of New South Wales, Kensington, New South Wales 2052, Australia.
Vanessa
V
Venturi
Complex Systems in Biology Group, Centre for Vascular Research, University of New South Wales, Kensington, New South Wales 2052, Australia.
Miles P
MP
Davenport
Department of Immunobiology and, the Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85724 and the BIO-5 Institute, University of Arizona, Tucson ,AZ 85719.
Janko
J
Nikolich-Zugich
D000818:Animals; D000831:Animals, Newborn; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology*; D002999:Clone Cells; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D019143:Evolution, Molecular; D018259:Herpesvirus 1, Human / Q000276:immunology; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D008136:Longevity / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology; D014759:Viral Envelope Proteins / Q000096:biosynthesis
D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D007135:Immunoglobulin Variable Region; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus
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