Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly

Sine Reker Hadrup, Jan Strindhall, Tania Køllgaard, Tina Seremet, Boo Johansson, Graham Pawelec, Per thor Straten, Anders Wikby

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

The age-associated decrease in functionality of the human immune system is thought to have a negative impact on the capacity to provide protection against infection, in turn leading to increased incidence of mortality. In a previous longitudinal study of octogenarians, we identified an immune risk phenotype (IRP) in the very elderly defined by an inverted CD4/CD8 ratio, which was associated with increased mortality and persistent CMV infection. In this study, we analyzed the CD8 clonal composition of nonagenarians and middle-aged individuals. An increased number of CD8 T cell clones was observed in the nonagenarians, and was associated with CMV-seropositivity. Surprisingly, CMV-seropositive nonagenarians with the IRP had a significantly lower number of clones compared with non-IRP individuals. The decrease in clone numbers in IRP individuals was associated with shorter survival time. MHC/peptide multimer staining indicated that the frequency of CMV-specific T cells was higher in nonagenarians than in the middle-aged, but the ratio of functionally intact cells was significantly lower. The lowest ratio of functional CMV-specific T cells was found in an IRP individual. A thorough longitudinal analysis of the CMV-specific T cells in nonagenarians showed a stable pattern with respect to frequency, phenotype, and clonal composition. We hypothesize that the number of different CD8 T cell clonal expansions increases as the individual ages, possibly, as a compensatory mechanism to control latent infections, e.g., CMV, but eventually a point is reached where clonal exhaustion leads to shrinkage of the CD8 clonal repertoire, associated with decreased survival.
Original languageEnglish
JournalJournal of Immunology
Volume176
Issue number4
Pages (from-to)2645-2653
Number of pages9
ISSN0022-1767
DOIs
Publication statusPublished - 2006
Externally publishedYes

Keywords

  • Immunology
  • adult
  • aged
  • article
  • CD4 CD8 ratio
  • CD8+ T lymphocyte
  • cell survival
  • clonal variation
  • controlled study
  • female
  • human
  • human cell
  • immune system
  • infection
  • infection sensitivity
  • latent virus infection
  • longitudinal study
  • lymphocyte function
  • major histocompatibility complex
  • male
  • mortality
  • normal human
  • phenotype
  • priority journal
  • T lymphocyte
  • Aged, 80 and over
  • Aging
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Clone Cells
  • Cytomegalovirus
  • Cytomegalovirus Infections
  • Female
  • Humans
  • Interferon Type II
  • Longitudinal Studies
  • Male
  • Phenotype
  • Receptors, Antigen, T-Cell
  • Interferon-gamma
  • 82115-62-6 Interferon-gamma
  • IMMUNOLOGY
  • IMMUNE RISK PHENOTYPE
  • SWEDISH NONA IMMUNE
  • LYMPHOCYTE SUBPOPULATIONS
  • OCTO-IMMUNE
  • MEMORY
  • AGE
  • EXPANSIONS
  • INFECTION
  • SUBSETS
  • OLD
  • cytomegalovirus infection Cytomegalovirus Infections (MeSH) viral disease, infectious disease pathology, mortality, immunology
  • dsDNA Viruses Viruses Microorganisms (Double-Stranded DNA Viruses, Microorganisms, Viruses) - Herpesviridae [03115] Cytomegalovirus genus
  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common middle age, aged/80 and over female, male
  • MHC
  • 10064, Biochemistry studies - Proteins, peptides and amino acids
  • 12502, Pathology - General
  • 15002, Blood - Blood and lymph studies
  • 15004, Blood - Blood cell studies
  • 24500, Gerontology
  • 33502, Virology - General and methods
  • 34502, Immunology - General and methods
  • 34508, Immunology - Immunopathology, tissue immunology
  • 36001, Medical and clinical microbiology - General and methods
  • 36006, Medical and clinical microbiology - Virology
  • Human Medicine, Medical Sciences
  • CD8 T-cell immune system, blood and lymphatics
  • Clinical Immunology
  • Geriatrics
  • Infection

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