title: IFNγ⁻TNFα⁻IL2⁻MIP1α⁻CD107a⁺PRF1⁺ CD8 pp65-Specific T-Cell Response Is Independently Associated With Time to Death in Elderly Humans.
abstract: Persistent cytomegalovirus (CMV) infection has been suggested to be a major driving force in the immune deterioration and an underlying source of age-related diseases in the elderly. CMV antibody titers are associated with lower responses to vaccination, cardiovascular diseases, frailty, and mortality. CMV infection is also associated with shorter T-cell telomeres and replicative senescence. Although an age-related deregulation of CMV-specific T-cell responses could be an underlying cause of the relationship between CMV and immune defects, strong and polyfunctional responses are observed in elderly individuals, casting uncertainty on their direct role in age-related immune frailty. In this study, we longitudinally followed a cohort of healthy donors aged over 50 years, assessing their mortality rates and time to death during a 2-year period. Specific T-cell responses to the immunodominant antigen pp65 (IFNγ, TNFα, IL2, MIP1α, CD107a, and perforin production) were analyzed at the beginning of the 2-year observation period. A cytotoxic CD8 pp65-specific T-cell response, without cytokine or chemokine coexpression, was independently associated with all-cause mortality in these elderly individuals. This pp65-specific CD8 T-cell response could be a useful tool to identify individuals with depressed immune function and a higher risk of death.
authors.affiliation: Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain. Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Sevilla, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Ferrando-Martínez
authors.affiliation: Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Sevilla, Spain.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Ruiz-Mateos
authors.affiliation: Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Casazza
authors.affiliation: Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Sevilla, Spain.
authors.forename: Rebeca S
authors.initials: RS
authors.lastname: de Pablo-Bernal
authors.affiliation: Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Sevilla, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Dominguez-Molina
authors.affiliation: Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain.
authors.forename: M Ángeles
authors.initials: MÁ
authors.lastname: Muñoz-Fernández
authors.affiliation: Internal Medicine Service, Hospital San Juan de Dios del Aljarafe, Bormujos, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Delgado
authors.affiliation: Internal Medicine Service, Hospital San Juan de Dios del Aljarafe, Bormujos, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: de la Rosa
authors.affiliation: Department of Cellular Immunology, IMIBIC-Reina Sofía University Hospital, University of Córdoba, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Solana
authors.affiliation: Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.affiliation: Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Sevilla, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Leal
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002097:C-Reactive Protein / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D002423:Cause of Death; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000401:mortality*; D003598:Cytoskeletal Proteins; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D054353:Perforin / Q000276:immunology*; D010641:Phenotype; D010750:Phosphoproteins / Q000276:immunology*; D012307:Risk Factors; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D007376:Interleukin-2; D052118:Lysosomal-Associated Membrane Protein 1; C502943:MAFIP protein, human; C510468:PRF1 protein, human; D010750:Phosphoproteins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D054353:Perforin; D007371:Interferon-gamma; D002097:C-Reactive Protein
keywords: Aging; CMV; CMV-specific T-cell response; Mortality; Perforin