Age-associated increase of low-avidity cytomegalovirus-specific CD8 + T cells that re-express CD45RA

Stephen J. Griffiths, Natalie E. Riddell, Joanne Masters, Valentina Libri, Sian M. Henson, Anne Wertheimer, Diana Wallace, Stuart Sims, Laura Rivino, Anis Larbi, David M. Kemeny, Janko Nikolich-Zugich, Florian Kern, Paul Klenerman, Vince C. Emery, Arne N. Akbar

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

The mechanisms regulating memory CD8+ T cell function and homeostasis during aging are unclear. CD8+ effector memory T cells that re-express CD45RA increase considerably in older humans and both aging and persistent CMV infection are independent factors in this process. We used MHC class I tetrameric complexes that were mutated in the CD8 binding domain to identify CMV-specific CD8+ T cells with high Ag-binding avidity. In individuals who were HLA-A*0201, CD8+ T cells that expressed CD45RA and were specific for the pp65 protein (NLVPMVATV epitope) had lower avidity than those that expressed CD45RO and demonstrated decreased cytokine secretion and cytolytic potential after specific activation. Furthermore, low avidity NLVPMVATV-specific CD8+ T cells were significantly increased in older individuals. The stimulation of blood leukocytes with CMV lysate induced high levels of IFN-α that in turn induced IL-15 production. Moreover, the addition of IL-15 to CD45RA2 CD45RO+ CMV-specific CD8+ T cells induced CD45RA expression while Ag activated cells remained CD45RO+. This raises the possibility that non-specific cytokine-driven accumulation of CMV-specific CD8+CD45RA+ T cells with lower Ag-binding avidity may exacerbate the effects of viral reactivation on skewing the T cell repertoire in CMV-infected individuals during aging.

Original languageEnglish (US)
Pages (from-to)5363-5372
Number of pages10
JournalJournal of Immunology
Volume190
Issue number11
DOIs
StatePublished - Jun 1 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Griffiths, S. J., Riddell, N. E., Masters, J., Libri, V., Henson, S. M., Wertheimer, A., Wallace, D., Sims, S., Rivino, L., Larbi, A., Kemeny, D. M., Nikolich-Zugich, J., Kern, F., Klenerman, P., Emery, V. C., & Akbar, A. N. (2013). Age-associated increase of low-avidity cytomegalovirus-specific CD8 + T cells that re-express CD45RA. Journal of Immunology, 190(11), 5363-5372. https://doi.org/10.4049/jimmunol.1203267