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

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-? that in turn induced IL-15 production. Moreover, the addition of IL-15 to CD45RA(-)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.

SUBMITTER: Griffiths SJ

PROVIDER: S-EPMC3736312 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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

Griffiths Stephen J SJ Riddell Natalie E NE Masters Joanne J Libri Valentina V Henson Sian M SM Wertheimer Anne A Wallace Diana D Sims Stuart S Rivino Laura L Larbi Anis A Kemeny David M DM Nikolich-Zugich Janko J Kern Florian F Klenerman Paul P Emery Vince C VC Akbar Arne N AN

Journal of immunology (Baltimore, Md. : 1950) 20130501 11

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 CD45 ...[more]

PMID: 23636061

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Project description:Cytomegalovirus (CMV) infection elicits a strong T-cell immune response, which increases further during aging in a process termed "memory inflation." CMV downregulates the expression of HLA-A and HLA-B on the surface of infected cells to limit presentation of viral peptides to T-cells although HLA-C is relatively spared as it also engages with inhibitory killer immunoglobulin receptor receptors and therefore reduces lysis by natural killer cells. We investigated the magnitude and functional properties of CMV-specific CD8+ T-cells specific for 10 peptides restricted by HLA-C in a cohort of 53 donors between the age of 23 and 91?years. This was achieved via peptide stimulation of PBMCs followed by multicolor flow cytometry. Three peptides, derived from proteins generated in the immediate-early period of viral replication and restricted by HLA-Cw*0702, elicited strong immune responses, which increased substantially with age such that the average aggregate response represented 37% of the CD8+ T-cell pool within donors above 70?years of age. Remarkably, a single response represented 70% of the total CD8+ T-cell pool within a 91-year-old donor. HLA-Cw*0702-restricted CD8+ T-cell responses were immunodominant over HLA-A and HLA-B-restricted CMV-specific responses and did not show features of exhaustion such as PD-1 or CD39 expression. Indeed, such CTL exhibit a polyfunctional cytokine profile with co-expression of IFN-? and TNF-? and a strong cytotoxic phenotype with intracellular expression of perforin and granzymeB. Functionally, HLA-Cw*0702-restricted CTL show exceptionally high avidity for cognate peptide-HLA and demonstrate very early and efficient recognition of virally infected cells. These observations indicate that CD8+ T-cells restricted by HLA-C play an important role in the control of persistent CMV infection and could represent a novel opportunity for CD8+ T-cell therapy of viral infection within immunosuppressed patients. In addition, the findings provide further evidence for the importance of HLA-C-restricted T-cells in the control of chronic viral infection.

Dataset Information

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

Publications

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

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