title: 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.
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.
authors.affiliation: Tumor Immunology Group, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark. sir@cancer.dk
authors.forename: Sine Reker
authors.initials: SR
authors.lastname: Hadrup
authors.forename: Jan
authors.initials: J
authors.lastname: Strindhall
authors.forename: Tania
authors.initials: T
authors.lastname: Køllgaard
authors.forename: Tina
authors.initials: T
authors.lastname: Seremet
authors.forename: Boo
authors.initials: B
authors.lastname: Johansson
authors.forename: Graham
authors.initials: G
authors.lastname: Pawelec
authors.forename: Per
authors.initials: P
authors.lastname: thor Straten
authors.forename: Anders
authors.initials: A
authors.lastname: Wikby
mesh_terms: D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology*; D002999:Clone Cells / Q000166:cytology / Q000276:immunology; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000401:mortality* / Q000821:virology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
chemical_list: D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma