Telomere Length as an Indicator of the Robustness of B- and T-Cell Response to Influenza in Older Adults.

BACKGROUND Telomeres provide a key mechanism for protecting the integrity of chromosomes and their attrition after cell division and during aging are evident in lymphocytes. However, the significance of telomere shortening in age-associated decline of immune function is unknown. METHODS We selected 22 HLA-A2-positive healthy older adults who have relatively short or long telomere lengths to compare their antibody response against the influenza vaccine, and their CD8(+) T-cell response against an influenza antigen. RESULTS B cells from individuals with a robust antibody response to the influenza vaccine had significantly longer telomeres than those with a poor antibody response. Monocyte-derived antigen-presenting cells of both short and long telomere groups induced similar expansions of influenza M1-specific CD8(+) T cells. Vaccination did not increase M1-specific CD8(+) T cells in blood, but M1-specific CD8(+) T cells from the long telomere group exhibited significantly greater expansion in vitro than those from the short telomere group. Finally, M1-specific CD8(+) T cells that underwent more expansions had significantly longer telomeres than cells with fewer divisions. CONCLUSIONS Telomere length is positively associated with a robust lymphocyte response, and telomere attrition may contribute to the age-associated decline of adaptive immunity.

[1]  Luigi Ferrucci,et al.  Age-associated telomere attrition of lymphocytes in vivo is co-ordinated with changes in telomerase activity, composition of lymphocyte subsets and health conditions. , 2015, Clinical science.

[2]  E. Slagboom,et al.  Latent Infection with Cytomegalovirus Is Associated with Poor Memory CD4 Responses to Influenza A Core Proteins in the Elderly , 2014, The Journal of Immunology.

[3]  A. Díaz,et al.  A comparative review of aging and B cell function in mice and humans. , 2013, Current opinion in immunology.

[4]  D. Murasko,et al.  Intrinsic defects in CD8 T cells with aging contribute to impaired primary antiviral responses , 2013, Experimental Gerontology.

[5]  C. Weyand,et al.  Understanding immunosenescence to improve responses to vaccines , 2013, Nature Immunology.

[6]  G. Pawelec,et al.  The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines. , 2012, Vaccine.

[7]  N. Weng.  Telomeres and immune competency. , 2012, Current opinion in immunology.

[8]  Mark M. Davis,et al.  Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies. , 2011, The Journal of clinical investigation.

[9]  L. Fried,et al.  Frailty is associated with impairment of vaccine-induced antibody response and increase in post-vaccination influenza infection in community-dwelling older adults. , 2011, Vaccine.

[10]  J. McElhaney,et al.  Influenza vaccine responses in older adults , 2011, Ageing Research Reviews.

[11]  S. Savage,et al.  The genetics and clinical manifestations of telomere biology disorders , 2010, Genetics in Medicine.

[12]  R. Cawthon,et al.  Telomere length in blood, buccal cells, and fibroblasts from patients with inherited bone marrow failure syndromes , 2010, Aging.

[13]  E. Wherry,et al.  Cell-Intrinsic Defects in the Proliferative Response of Antiviral Memory CD8 T Cells in Aged Mice upon Secondary Infection , 2010, The Journal of Immunology.

[14]  Sarah E. Jackson,et al.  Cytomegalovirus Infection Reduces Telomere Length of the Circulating T Cell Pool , 2010, The Journal of Immunology.

[15]  M. Armanios.  Syndromes of telomere shortening. , 2009, Annual review of genomics and human genetics.

[16]  Z. Ndhlovu,et al.  Development of an Artificial-Antigen-Presenting-Cell-Based Assay for the Detection of Low-Frequency Virus-Specific CD8+ T Cells in Whole Blood, with Application for Measles Virus , 2009, Clinical and Vaccine Immunology.

[17]  I. Dokal,et al.  Dyskeratosis congenita, stem cells and telomeres , 2009, Biochimica et biophysica acta.

[18]  N. Nanlohy,et al.  Progressive telomere shortening of Epstein-Barr virus-specific memory T cells during HIV infection: contributor to exhaustion? , 2008, The Journal of infectious diseases.

[19]  N. Weng.  Telomere and adaptive immunity , 2008, Mechanisms of Ageing and Development.

[20]  N. Weng.  Aging of the immune system: how much can the adaptive immune system adapt? , 2006, Immunity.

[21]  T. de Lange,et al.  Shelterin: the protein complex that shapes and safeguards human telomeres. , 2005, Genes & development.

[22]  R. Hodes,et al.  Analysis of Telomere Length and Telomerase Activity , 2004, Current protocols in immunology.

[23]  G. Pawelec,et al.  Large Numbers of Dysfunctional CD8+ T Lymphocytes Bearing Receptors for a Single Dominant CMV Epitope in the Very Old , 2003, Journal of Clinical Immunology.

[24]  F. Sallusto,et al.  Opinion-decision making in the immune system: Progressive differentiation and selection of the fittest in the immune response , 2002, Nature Reviews Immunology.

[25]  R. Hodes,et al.  Telomeres in T and B cells , 2002, Nature Reviews Immunology.

[26]  J. Skurnick,et al.  Telomere Length in the Newborn , 2002, Pediatric Research.

[27]  Walther Parson,et al.  Lack of Antibody Production Following Immunization in Old Age: Association with CD8+CD28− T Cell Clonal Expansions and an Imbalance in the Production of Th1 and Th2 Cytokines1 , 2002, The Journal of Immunology.

[28]  R. Cawthon.  Telomere measurement by quantitative PCR. , 2002, Nucleic acids research.

[29]  W. O'Fallon,et al.  Value of Immunological Markers in Predicting Responsiveness to Influenza Vaccination in Elderly Individuals , 2001, Journal of Virology.

[30]  U. Klotz,et al.  Telomere length in different tissues of elderly patients , 2000, Mechanisms of Ageing and Development.

[31]  E. Blackburn,et al.  Telomere states and cell fates , 2000, Nature.

[32]  R. Hodes,et al.  Lineage-Specific Telomere Shortening and Unaltered Capacity for Telomerase Expression in Human T and B Lymphocytes with Age , 2000, The Journal of Immunology.

[33]  Nathalie Rufer,et al.  Telomere Fluorescence Measurements in Granulocytes and T Lymphocyte Subsets Point to a High Turnover of Hematopoietic Stem Cells and Memory T Cells in Early Childhood , 1999, The Journal of experimental medicine.

[34]  H. Schwartz,et al.  Comparison of chromosome telomere integrity in multiple tissues from subjects at different ages. , 1998, Cancer genetics and cytogenetics.

[35]  C. Greider.  Telomeres and senescence: The history, the experiment, the future , 1998, Current Biology.

[36]  R. Hodes,et al.  Telomere lengthening and telomerase activation during human B cell differentiation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[37]  C. Harley,et al.  Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. , 1996, AIDS.

[38]  H. Ostrer,et al.  Shortened telomeres in clonally expanded CD28-CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts. , 1996, Journal of immunology.

[39]  G. Roos,et al.  Telomerase activation in normal B lymphocytes and non-Hodgkin's lymphomas. , 1996, Blood.

[40]  C. Harley,et al.  Telomere length and replicative aging in human vascular tissues. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[41]  B L Levine,et al.  Human naive and memory T lymphocytes differ in telomeric length and replicative potential. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[42]  R. Effros,et al.  Decline in CD28+ T cells in centenarians and in long-term T cell cultures: A possible cause for both in vivo and in vitro immunosenescence , 1994, Experimental Gerontology.

[43]  C B Harley,et al.  Telomere length predicts replicative capacity of human fibroblasts. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[44]  C. Harley,et al.  Telomeres shorten during ageing of human fibroblasts , 1990, Nature.