Elderly Humans Response to Primary Viral Infection in Numbers Are Associated with the Immune Low Thymic Activity and Dendritic Cell

Immunological competence declines progressively with age, resulting in increased susceptibility of the elderly to infection and impaired responses to vaccines. Underlying mechanisms remain largely obscure as they have been related to complex, individual systemic immune properties that are challenging to investigate. In this study, we explored age-related changes in human immunity during a primary virus infection experimentally induced by immunization with live-attenuated yellow fever (YF) vaccine. Ap-plying detailed serology, advanced FACS analysis, and systems biology, we discovered that aged subjects developed fewer neutralizing Abs, mounted diminished YF-specific CD8 + T cell responses, and showed quantitatively and qualitatively altered YF-specific CD4 + T cell immunity. Among numerous immune signatures, low in vivo numbers of naive CD4 + recent thymic emigrants and peripheral dendritic cells correlated well with reduced acute responsiveness and altered long-term persistence of human cellular immunity to YF vaccination. Hence, we reveal in this article that essential elements of immune responses such as recent thymic emigrants and dendritic cells strongly relate to productive immunity in the elderly, providing a conceivable explanation for diminished responsiveness to vaccination with neoantigens and infection with de novo pathogens in the aged population. The Journal of Immunology , 2015, 195: 000–000.

[1]  V. Appay,et al.  Pathogen-Specific T Cell Polyfunctionality Is a Correlate of T Cell Efficacy and Immune Protection , 2015, PloS one.

[2]  P. Desprès,et al.  Viral entry route determines how human plasmacytoid dendritic cells produce type I interferons , 2015, Science Signaling.

[3]  Rustom Antia,et al.  Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination , 2015, Proceedings of the National Academy of Sciences.

[4]  S. Buus,et al.  CD8+ T Cells Complement Antibodies in Protecting against Yellow Fever Virus , 2015, The Journal of Immunology.

[5]  J. Singer,et al.  Immune activation alters cellular and humoral responses to yellow fever 17D vaccine. , 2014, The Journal of clinical investigation.

[6]  V. Appay,et al.  Naive T cells: The crux of cellular immune aging? , 2014, Experimental Gerontology.

[7]  M. Blackman,et al.  Impact of ageing on the response and repertoire of influenza virus-specific CD4 T cells , 2014, Immunity & Ageing.

[8]  Ruth R. Montgomery,et al.  Age-dependent dysregulation of innate immunity , 2013, Nature Reviews Immunology.

[9]  G. Pawelec,et al.  Human T Cell Aging and the Impact of Persistent Viral Infections , 2013, Front. Immunol..

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

[11]  J. K. Sandberg,et al.  Temporal Dynamics of the Primary Human T Cell Response to Yellow Fever Virus 17D As It Matures from an Effector- to a Memory-Type Response , 2013, The Journal of Immunology.

[12]  P. van Damme,et al.  Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination. , 2013, Vaccine.

[13]  M. Ventresca,et al.  The Polyfunctionality of Human Memory CD8+ T Cells Elicited by Acute and Chronic Virus Infections Is Not Influenced by Age , 2012, PLoS pathogens.

[14]  M. Davenport,et al.  Lifelong Persistent Viral Infection Alters the Naive T Cell Pool, Impairing CD8 T Cell Immunity in Late Life , 2012, The Journal of Immunology.

[15]  P. Patel,et al.  Advanced Yellow Fever Virus Genome Detection in Point-of-Care Facilities and Reference Laboratories , 2012, Journal of Clinical Microbiology.

[16]  M. Smithey,et al.  Age-related changes in CD8 T cell homeostasis and immunity to infection. , 2012, Seminars in immunology.

[17]  B. Grubeck‐Loebenstein,et al.  Vaccines for the elderly. , 2012, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[18]  O. Lesur,et al.  Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. , 2012, Seminars in immunology.

[19]  A. Thiel,et al.  The early cellular signatures of protective immunity induced by live viral vaccination , 2012, European journal of immunology.

[20]  L. Čičin-Šain,et al.  Cytomegalovirus Infection Impairs Immune Responses and Accentuates T-cell Pool Changes Observed in Mice with Aging , 2012, PLoS pathogens.

[21]  J. Virchow,et al.  Plasmacytoid dendritic cells and their Toll-like receptor 9 expression selectively decrease with age. , 2012, Human immunology.

[22]  T. Monath.  Review of the risks and benefits of yellow fever vaccination including some new analyses , 2012, Expert review of vaccines.

[23]  C. Weyand,et al.  Immune aging and autoimmunity , 2012, Cellular and Molecular Life Sciences.

[24]  P. Bredenbeek,et al.  Elderly Subjects Have a Delayed Antibody Response and Prolonged Viraemia following Yellow Fever Vaccination: A Prospective Controlled Cohort Study , 2011, PloS one.

[25]  M. Blackman,et al.  The narrowing of the CD8 T cell repertoire in old age. , 2011, Current opinion in immunology.

[26]  Sudhir Gupta,et al.  Impact of aging on dendritic cell functions in humans , 2011, Ageing Research Reviews.

[27]  A. Vallejo.  Immunological hurdles of ageing: Indispensable research of the human model , 2011, Ageing Research Reviews.

[28]  B. Grubeck‐Loebenstein,et al.  Persistent viral infections and immune aging , 2011, Ageing Research Reviews.

[29]  Ruth R. Montgomery,et al.  Impaired interferon signaling in dendritic cells from older donors infected in vitro with West Nile virus. , 2011, The Journal of infectious diseases.

[30]  M. Smithey,et al.  Increased apoptosis, curtailed expansion and incomplete differentiation of CD8+ T cells combine to decrease clearance of L. monocytogenes in old mice , 2011, European journal of immunology.

[31]  R. Ahmed,et al.  Insights into human CD8+ T‐cell memory using the yellow fever and smallpox vaccines , 2011, Immunology and cell biology.

[32]  Mario Roederer,et al.  SPICE: Exploration and analysis of post‐cytometric complex multivariate datasets , 2011, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[33]  M. Loeb,et al.  Surface Phenotype and Functionality of WNV Specific T Cells Differ with Age and Disease Severity , 2010, PloS one.

[34]  C. Wiley,et al.  Immune Response to the West Nile Virus in Aged Non-Human Primates , 2010, PloS one.

[35]  F. Tacke,et al.  Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults , 2010, BMC Immunology.

[36]  M. Mori,et al.  Loss of Naive T Cells and Repertoire Constriction Predict Poor Response to Vaccination in Old Primates , 2010, The Journal of Immunology.

[37]  C. Rice,et al.  The Yellow Fever Virus Vaccine Induces a Broad and Polyfunctional Human Memory CD 8 T Cell Response 1 , 2009 .

[38]  C. Wiley,et al.  Key role of T cell defects in age-related vulnerability to West Nile virus , 2009, The Journal of experimental medicine.

[39]  M. Blackman,et al.  T-cell immunosenescence: lessons learned from mouse models of aging , 2009, Trends in Immunology.

[40]  Bastian R. Angermann,et al.  Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses , 2008, The Journal of experimental medicine.

[41]  M. Cetron,et al.  Case of yellow fever vaccine--associated viscerotropic disease with prolonged viremia, robust adaptive immune responses, and polymorphisms in CCR5 and RANTES genes. , 2008, The Journal of infectious diseases.

[42]  M. Drebot,et al.  The Memory T Cell Response to West Nile Virus in Symptomatic Humans following Natural Infection Is Not Influenced by Age and Is Dominated by a Restricted Set of CD8+ T Cell Epitopes1 , 2008, The Journal of Immunology.

[43]  J. Altman,et al.  Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. , 2008, Immunity.

[44]  M. Roederer,et al.  T-cell quality in memory and protection: implications for vaccine design , 2008, Nature Reviews Immunology.

[45]  Mushtaq Ahmed,et al.  Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus , 2008, The Journal of experimental medicine.

[46]  C. Jean,et al.  Risk Factors for West Nile Virus Neuroinvasive Disease, California, 2005 , 2007, Emerging infectious diseases.

[47]  F. Borràs,et al.  Reduced numbers of plasmacytoid dendritic cells in aged blood donors , 2007, Experimental Gerontology.

[48]  Mario Roederer,et al.  Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major , 2007, Nature Medicine.

[49]  H. Robinson,et al.  Multiple-Cytokine-Producing Antiviral CD4 T Cells Are Functionally Superior to Single-Cytokine-Producing Cells , 2007, Journal of Virology.

[50]  H. Naim,et al.  Use of viral vectors for the development of vaccines , 2007, Expert review of vaccines.

[51]  D. Cooper,et al.  CD127+CCR5+CD38+++ CD4+ Th1 Effector Cells Are an Early Component of the Primary Immune Response to Vaccinia Virus and Precede Development of Interleukin-2+ Memory CD4+ T Cells , 2006, Journal of Virology.

[52]  M. Cetron,et al.  Yellow Fever 17D Vaccine Safety and Immunogenicity in the Elderly , 2005, Human vaccines.

[53]  D. Murasko,et al.  Response of aged mice to primary virus infections , 2005, Immunological reviews.

[54]  M. Pierer,et al.  Post‐thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults , 2005, European journal of immunology.

[55]  Robert T. Chen,et al.  Yellow fever vaccine: an updated assessment of advanced age as a risk factor for serious adverse events. , 2005, Vaccine.

[56]  K. Pfeiffer,et al.  Insufficient protection for healthy elderly adults by tetanus and TBE vaccines. , 2005, Vaccine.

[57]  F. Guirakhoo,et al.  Chimeric live, attenuated vaccine against Japanese encephalitis (ChimeriVax-JE): phase 2 clinical trials for safety and immunogenicity, effect of vaccine dose and schedule, and memory response to challenge with inactivated Japanese encephalitis antigen. , 2003, The Journal of infectious diseases.

[58]  J. Myśliwska,et al.  Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination--an impact of immunosenescence. , 2003, Vaccine.

[59]  J. Peiris,et al.  Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study , 2003, The Lancet.

[60]  T. Monath,et al.  Comparative safety and immunogenicity of two yellow fever 17D vaccines (ARILVAX and YF-VAX) in a phase III multicenter, double-blind clinical trial. , 2002, The American journal of tropical medicine and hygiene.

[61]  E. Gardner,et al.  Age-associated decrease in virus-specific CD8+ T lymphocytes during primary influenza infection , 2002, Mechanisms of Ageing and Development.

[62]  Andreas Radbruch,et al.  Two Subsets of Naive T Helper Cells with Distinct T Cell Receptor Excision Circle Content in Human Adult Peripheral Blood , 2002, The Journal of experimental medicine.

[63]  E. Leventhal,et al.  Aging, immunity, and cancer. , 2000, Cancer control : journal of the Moffitt Cancer Center.

[64]  C. Franceschi,et al.  Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. , 2000, Blood.

[65]  Matthias Niedrig,et al.  Development of viremia and humoral and cellular parameters of immune activation after vaccination with yellow fever virus strain 17D: A model of human flavivirus infection , 1998, Journal of medical virology.

[66]  G. Hartmann,et al.  In vivo synthesis of tumor necrosis factor-alpha in healthy humans after live yellow fever vaccination. , 1998, The Journal of infectious diseases.

[67]  S. Spector,et al.  Yellow fever vaccine , 1972, Archiv für die gesamte Virusforschung.

[68]  Vaccines and vaccination against yellow fever: WHO Position Paper, June 2013--recommendations. , 2015, Vaccine.

[69]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[70]  Eva K. Lee,et al.  Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans , 2009, Nature Immunology.

[71]  R. Walder,et al.  Replication of virulent and attenuated strains of yellow fever virus in human monocytes and macrophage-like cells (U937) , 2005, Archives of Virology.

[72]  Rachel Barwick Eidex.  History of thymoma and yellow fever vaccination. , 2004, Lancet.

[73]  J. Phair,et al.  Ageing and infection. , 1988, Ciba Foundation symposium.

[74]  T. Monath,et al.  Persistence of neutralizing antibody 30-35 years after immunization with 17D yellow fever vaccine. , 1981, Bulletin of the World Health Organization.