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Age-related deregulation of naive T cell homeostasis in elderly humans

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Abstract

Immunosenescence is characterized by phenotypic and functional changes of effector memory T cells. In spite of the well-described senescent defects of these experienced T cells, immune responses to new pathogens are also deeply affected in elderly humans, suggesting that naive T cells could also show age-related defects. It has been reported in both, animal models and humans, alterations of the naive T cell turnover associated to advanced age or low thymic function. However, as far as we know, homeostatic mechanisms involved in the deregulation of naive T cell peripheral dynamics and their consequences are still not well understood. Thus, the aim of our study was to analyze homeostatic parameters of peripheral naive T cells and their relationship with thymic function in young and elderly humans. Our results show that lower naive T cell numbers were associated with a lower thymic function and higher activation and proliferating naive T cell levels. We then analyzed sjTREC numbers and relative telomere length from sorted naive T cells. Our results show that the aberrant activation and proliferation status was related to lower sjTREC numbers (a peripheral proliferation marker) and both, higher CD57 expression levels and shortened telomeres (replicative senescence-related markers). Elderly individuals show a greater contraction of the CD8 naive T cell numbers and all homeostatic alterations were more severe in this compartment. In addition, we found that low functional thymus show a CD4-biased thymocyte production. Taken together, our results suggest a homeostatic deregulation, affecting mostly the naive CD8 T cell subset, leading to the accumulation of age-associated defects in, otherwise, phenotypically naive T cells.

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References

  • Akbar AN, Fletcher JM (2005) Memory T cell homeostasis and senescence during aging. Curr Opin Immunol 17:480–485

    Article  PubMed  CAS  Google Scholar 

  • Almeida AR, Rocha B, Freitas AA, Tarichot C (2005) Homeostasis of T cell numbers: from thymus production to peripheral compartimentalization and the indexation of regulatory T cells. Semin Immunol 17:239–249

    Article  PubMed  CAS  Google Scholar 

  • Armanios M, Alder JK, Parry EM, Karim B, Strong MA, Greider CW (2009) Short telomeres are sufficient to cause the degenerative defects associated with aging. Am J Hum Gen 85:823–832

    Article  CAS  Google Scholar 

  • Aspinal R (2003) Age-related changes in the function of T cells. Microsc Res Tech 62:508–513

    Article  Google Scholar 

  • Aw D, Silva AB, Palmer DB (2007) Immunosenescence: emerging challenges for an ageing population. Immunology 120:435–446

    Article  PubMed  CAS  Google Scholar 

  • Barbour JD, Ndhlovu LC, Xuan Tan Q, Ho T, Epling L, Bredt BM, Levy JA, Hecht FM, Sinclair E (2009) High CD8+ T cell activation marks a less differentiated HIV-1 specific CD8+ T cell response that is not altered by suppression of viral replication. PLoS One 4:e4408

    Article  PubMed  Google Scholar 

  • Bauer HM, Ting Y, Greer C, Chambers JC, Tashiro CJ, Chimera J, Reingold A, Manos MM (1991) Genital human papillomavirus infection in female university student as determined by PCR-based method. JAMA 265:472–477

    Article  PubMed  CAS  Google Scholar 

  • Bourgeois C, Hao Z, Rajewsky K, Potocnik AJ, Stockinger B (2008) Ablation of thymic export causes accelerated decay of naive CD4 T cells in the periphery because of activation by environmental antigen. Proc Natl Acad Sci USA 105:8691–8696

    Article  PubMed  CAS  Google Scholar 

  • Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, Casazza JP, Kuruppu J, Migueles SA, Connors M, Roederer M, Douek DC, Kroup RA (2003) Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8 T cells. Blood 101:2711–2720

    Article  PubMed  CAS  Google Scholar 

  • Cawthon RM (2002) Telomere measurement by quantitative PCR. Nucleic Acids Res 30:e47

    Article  PubMed  Google Scholar 

  • Chattopadhyay PK, Betts MR, Price DA, Gostick E, Horton H, Roederer M, De Rosa SC (2009) The cytolytic enzymes granzyme A, granzyme B, and perforina: expression patterns, cell distribution, and their relationship to cell maturity and bright CD57 expression. J Leukoc Biol 85:88–97

    Article  PubMed  CAS  Google Scholar 

  • Chiodi H (1940) The relationship between the thymus and the sexual organs. Endocrinology 26:107–116

    Article  CAS  Google Scholar 

  • Cicin-Saint L, Messaoudi I, Park B, Currier N, Planer S, Fischer M, Tackitt S, Nikolich-Zugich D, Legasse A, Axthelm MK, Picker LJ, Mori M, Nikolich-Zugich J (2007) Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates. Proc Natl Acad Sci USA 104:19960–19965

    Article  Google Scholar 

  • Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Ouslander JG, Weyand CM, Goronzy JJ (2008) T cell subset-specific susceptibility to aging. Clin Immunol 127:107–118

    Article  PubMed  CAS  Google Scholar 

  • Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690–695

    Article  PubMed  CAS  Google Scholar 

  • Ernst B, Lee DS, Chang JM, Sprent J, Surh CD (1999) The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11:173–181

    Article  PubMed  CAS  Google Scholar 

  • Ferrando-Martinez S, Franco JM, Hernandez A, Ordoñez A, Gutierrez E, Abad A, Leal M (2009) Thymopoiesis in elderly human is associated with systemic inflammatory status. AGE 31:87–97

    Article  PubMed  CAS  Google Scholar 

  • Ferrando-Martinez S, Ruiz-Mateos E, Leal M (2010a) CD27 and CCR7 expression on naive T cells, are both necessary? Immunol Lett 127:157–158

    Article  PubMed  CAS  Google Scholar 

  • Ferrando-Martinez S, Franco JM, Ruiz-Mateos E, Hernández A, Ordoñez A, Gutierrez E, Leal M (2010b) A reliable and simplified sj/beta-TREC ratio quantification method for human thymic output measurement. J Immunol Methods 352:111–117

    Article  PubMed  CAS  Google Scholar 

  • Franco JM, Rubio A, Martinez-Moya M, Leal M, Merchante E, Sánchez-Quijano A, Lissen E (2002) T-cell repopulation and thymic volumen in HIV-1 infected adult patients afther highly active antiretroviral therapy. Blood 99:3702–3706

    Article  PubMed  CAS  Google Scholar 

  • Gress RE, Deeks SG (2009) Reduced thymus activity and infection prematurely age the immune system. J Clin Invest 119:2884–2887

    Article  PubMed  CAS  Google Scholar 

  • Gruver AL, Hudson LL, Sempowski GD (2007) Immunosenescence of aging. J Pathol 211:144–156

    Article  PubMed  CAS  Google Scholar 

  • Hara M, Matsuzaki Y, Shimizu T, Tomita M, Ayabe T, Enomoto Y, Onitsuka T (2007) Preoperative peripheral naive/memory ration and prognosis of nonsmall-cell lung cancer patients. Ann Thorac Cardiovasc Surg 13:384–390

    PubMed  Google Scholar 

  • Haynes BF, Market ML, Sempowski GD, Patel DD, Hale LP (2000) The role of the thymus in immune reconstitution in aging, bone marrow transplantation and HIV-1 infection. Annu Rev Immunol 18:529–560

    Article  PubMed  CAS  Google Scholar 

  • Harris JM, Hazenberg MD, Poulin JF, Higuera-Alhino D, Schmidt D, Gotway M, McCune JM (2005) Multiparameter evaluation of human thymic function: interpretations and caveats. Clin Immunol 115:138–146

    Article  PubMed  CAS  Google Scholar 

  • Jameson SC (2002) Maintaining the norm: T-cell homeostasis. Nat Rev Immunol 2:547–556

    PubMed  CAS  Google Scholar 

  • Junge S, Cloeckener-Gruissem B, Zufferey R, Keisker A, Salgo B, Fauchere JC, Scherer F, Shalaby T, Grotzer M, Siler U, Seger R, Güngör T (2007) Correlation between recent thymic emigrants and CD31+ (PECAM-1) CD4+ T cells in normal individuals during aging and in lymphopenic children. Eur J Immunol 37:3270–3280

    Article  PubMed  CAS  Google Scholar 

  • Kilpatrick RD, Rickabaugh T, Hultin LE, Hultin P, Hausner MA, Detels R, Phair J, Jamieson BD (2008) Homeostasis of the naive CD4+ T cell compartment during aging. J Immunol 180:1499–1507

    PubMed  CAS  Google Scholar 

  • Kohler S, Thiel A (2008) Life after the thymus, CD31+ and CD31- human naive CD4+ T-cell subsets. Blood 113:769–774

    Article  PubMed  Google Scholar 

  • Li CR, Santoso S, Lo DD (2007) Quantitative analysis of T cell homeostatic proliferation. Cell Immunol 250:40–54

    Article  PubMed  CAS  Google Scholar 

  • Linton PJ, Dorshkind L (2004) Age related changes in lymphocyte development and function. Nat Immunol 5:133–139

    Article  PubMed  CAS  Google Scholar 

  • Miller RA (1996) The aging immune system: primer and prospectus. Science 273:70–74

    Article  PubMed  CAS  Google Scholar 

  • Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, Witkowski J, Fulbright J, Weyand CM, Goronzy JJ (2005) The influence of age on T cell generation and TCR diversity. J Immunol 174:7446–7452

    PubMed  CAS  Google Scholar 

  • Nickolich-Zugich J (2008) Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol 8:512–522

    Article  Google Scholar 

  • Nobile M, Correa R, Borghans JA, D’Agostino C, Schneider P, De Boer RJ, Pantaleo G, Swiss HIV Cohort Study (2004) De novo T cell generation in patients at different ages and stages of HIV-1 disease. Blood 104:470–477

    Article  PubMed  CAS  Google Scholar 

  • Pawelec G, Akbar A, Caruso C, Effros R, Grucbeck-Loebenstein B, Wikby A (2004) Is immunosenescence infectious? Trends Immunol 25:406–410

    Article  PubMed  CAS  Google Scholar 

  • Pawelec G, Koch S, Gouttefangeas C, Wikby A (2006) Immunorejuvenation in the elderly. Rejuvenation Res 9:111–116

    Article  PubMed  CAS  Google Scholar 

  • Petrovas C, Chaon B, Ambrozak DR, Price DA, Melenhorst JJ, Hill BJ, Geldmacher C et al (2009) Differential association of programmed death-1 and CD57 with ex vivo survival of CD8 T cells in HIV infection. J Immunol 183:1120–1132

    Article  PubMed  CAS  Google Scholar 

  • Prelog M, Keller M, Geiger R, Brandstätter A, Würzner R, Schweigmann U, Zlamy M, Zimmerhackl LB, Grubeck-Loebenstein B (2009) Thymectomy in early childhood: significant alterations of the CD4(+)CD45RA(+)CD62L(+) T cell compartment in later life. Clin Immunol 130:123–132

    Article  PubMed  CAS  Google Scholar 

  • Takada K, Jameson SC (2009) Naive T cell homeostasis: from awareness of space to a sense of place. Nat Rev Immunol 9:823–832

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Authors want to thank Dr. Ricardo Pardal and the Laboratorio of Investigaciones Biológicas (LIB) for their priceless help in cell sorting. We also want to thank all the Cardiac surgery staff for their kindness and patience. SFM and ERM have grants from the Fondo de Investigaciones Sanitarias (FIS06/00176 and CP08/00172, respectively). This study is supported by Redes Temáticas de Investigación en SIDA (ISCIII RETIC RD06/0006/0021), Redes Temáticas de Cardiovascular (ISCIII RECAVA RD06/0014), Proyecto de Excelencia, Consejería de Innovación, Ciencia y Empresa (P06-CTS-01579) and Consejería de Salud, Servicio Andaluz de Salud (156/2006 and PI0366/07).

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Authors and Affiliations

  1. Laboratory of Immunovirology, Biomedicine Institute of Seville (IBIS). Service of Infectious Diseases, Virgen del Rocío University Hospital, Avda. Manuel Siurot s/n, 41013, Seville, Spain

    Sara Ferrando-Martínez, Ezequiel Ruiz-Mateos, Maria del Mar Rodríguez-Méndez & Manuel Leal

  2. Department of Clinical Biochemistry, IBIS/CSIC/University of Seville, Virgen del Rocío University Hospital, Seville, Spain

    Sara Ferrando-Martínez & Maria del Mar Rodríguez-Méndez

  3. Cardiac Surgery, Virgen del Rocio University Hospital, Seville, Spain

    Ana Hernández, Encarnación Gutiérrez & Antonio Ordoñez

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  1. Sara Ferrando-Martínez
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  2. Ezequiel Ruiz-Mateos
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  3. Ana Hernández
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  4. Encarnación Gutiérrez
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  5. Maria del Mar Rodríguez-Méndez
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  6. Antonio Ordoñez
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  7. Manuel Leal
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Correspondence to Manuel Leal.

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Fig. S1

Age-related drop of naive CD4 T cells. B) Differences in percentages of activation (CD38+HLADR+ expressing T cells, dark grey circles), replicative senescence (CD57+ expressing T cells, black circles) and proliferating (Ki67+ expressing T cells, light grey circles) naive CD4 T cells among the age groups. C) sj-TREC levels per naive CD4+ T cell between the age groups (grey circles) and Relative naive CD4+ T cell Telomere Length differences between the age groups (black circles). D) Relationship between peripheral percentage of Naive CD4+ T cells and their Relative Telomere Length. (GIF 0 kb)

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Ferrando-Martínez, S., Ruiz-Mateos, E., Hernández, A. et al. Age-related deregulation of naive T cell homeostasis in elderly humans. AGE 33, 197–207 (2011). https://doi.org/10.1007/s11357-010-9170-8

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  • DOI: https://doi.org/10.1007/s11357-010-9170-8

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