Thymopoiesis in elderly human is associated with systemic inflammatory status
- 87 Downloads
- 28 Citations
Abstract
Immunosenescence studies of age-related immune system damage focused on clinical lymphopenic situations or androgenic blockade have revealed new insights about adult human immune reconstitution. However, as far as we know, the extent of lymphopoiesis in the thymus of elderly humans remains unclear. To this effect, we have analyzed 65 adult human thymuses (from 36 to 81 years; median age 68.6 years) obtained from patients who underwent cardiac surgery. Our results show a correlation between CD4+CD8+ double-positive (DP) cells and both the age (inverse) and percentage (direct) of peripheral naive T cells, indicating that the thymus is still able to affect the peripheral lymphocyte pool even in the elderly. We also found significant correlation between the degree of thymopoiesis and the inflammation markers, as shown by the inverse correlations between DP and the percentage of neutrophils and IL-6 levels and the percentage of peripheral lymphocytes. Furthermore, in a multivariate linear regression the percentage of DP and IL-7 levels, but not age, were independently associated with the percentage of neutrophils. In conclusion, the thymus maintains, even in the elderly, an active thymopoiesis that rejuvenates the peripheral naive T-cell pool. Moreover, age-related thymopoietic decay is associated with the peripheral inflammation markers.
Keywords
Ageing T cell homeostasis Human thymus Immunosenescence Neutrophil Systemic inflammationNotes
Acknowledgements
The authors thank Ms. Maria del Mar Rodriguez for her excellent technical assistance and the anesthesia and surgical personnel for their kindness and patience. Sara Ferrando-Martínez has a grant from the Fondo de Investigaciones Sanitarias (FIS, FI06/00176). This study was supported by the Fundación para la Investigación y la Prevención del SIDA en España (FIPSE, 12481/05), Redes Temáticas de Investigación en SIDA (ISCIII RETIC RD06/0006/0021), Redes Temáticas Cardio-Vascular (ISCIII RECAVA, RD06/0014), Proyecto de Excelencia, Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía, Spain (P06-CTS-01579), Consejería de Salud, Servicio Andaluz de Salud (156/2006) and Consejería de Salud, Servicio Andaluz de Salud (PI0366/07).
References
- Aiello FB, Keller JR, Klarmann KD et al (2007) IL-7 induces myelopoiesis and erythropoiesis. J Immunol 178(3):1553–1563PubMedGoogle Scholar
- Aspinall R, Del Giudice G, Effros RB et al (2007) Challenges for vaccination in the elderly. Immun Ageing 4(1):9. doi: 10.1186/1742-4933-4-9 PubMedCrossRefGoogle Scholar
- Aw D, Silva AB, Palmer DB et al (2007) Immunosenescence: emerging challenges for an ageing population. Immunology 120(4):435–446. doi: 10.1111/j.1365-2567.2007.02555.x PubMedCrossRefGoogle Scholar
- Bauer HM, Ting Y, Greer C et al (1991) Genital human papillomavirus infection in female university student as determined by PCR-based method. JAMA 265:472–477. doi: 10.1001/jama.265.4.472 PubMedCrossRefGoogle Scholar
- Cambier J (2005) Immunosenescence: a problem of lymphopoiesis, homeostasis, microenvironment, and signaling. Immunol Rev 205:5–6. doi: 10.1111/j.0105-2896.2005.00276.x PubMedCrossRefGoogle Scholar
- Cicin-Sain L, Messaoudi I, Park B et al (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(50):19960–19965. doi: 10.1073/pnas.0705905104 PubMedCrossRefGoogle Scholar
- Cohen JJ, Duke RC, Fadok VA et al (1992) Apoptosis and programmed cell death in immunity. Annu Rev Immunol 10:267–293. doi: 10.1146/annurev.iy.10.040192.001411 PubMedCrossRefGoogle Scholar
- De la Rosa R, Leal M (2003) Thymic involvement in recovery of immunity among HIV-infected adults on highly active antirretroviral therapy. J Antimicrob Chemother 52(2):155–158. doi: 10.1093/jac/dkg311 PubMedCrossRefGoogle Scholar
- De Martinis M, Franceschi C, Monti D et al (2006) Inflammation markers predicting frailty and mortality in the elderly. Exp Mol Pathol 80(3):219–227. doi: 10.1016/j.yexmp.2005.11.004 PubMedCrossRefGoogle Scholar
- DelaRosa O, Pawelec G, Peralbo E et al (2006) Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity. Biogerontology 7(5-6):471–481. doi: 10.1007/s10522-006-9062-6 PubMedCrossRefGoogle Scholar
- Douek DC, McFarland RD, Keiser PH et al (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690–695. doi: 10.1038/25374 PubMedCrossRefGoogle Scholar
- Franco JM, Rubio A, Martinez-Moya M et al (2002) T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy. Blood 99(10):3702–3706. doi: 10.1182/blood.V99.10.3702 PubMedCrossRefGoogle Scholar
- Girard D, Beaulieu AD (1997) Absence of the IL-7 receptor component CDw127 indicates that gamma(c) expression alone is insufficient for IL-7 to modulate human neutrophil responses. Clin Immunol Immunopathol 83(3):264–271. doi: 10.1006/clin.1997.4341 PubMedCrossRefGoogle Scholar
- Goldberg GL, Zakrzewski JL, Perales MA et al (2007) Clinical strategies to enhance T cell reconstitution. Semin Immunol 19(5):289–296. doi: 10.1016/j.smim.2007.08.001 PubMedCrossRefGoogle Scholar
- Goldberg GL, Alpodogan O, Muriglan SJ et al (2007b) Enhanced immune reconstitution by sex steroid ablation following allogeneic hemopoietic stem cell transplantation. J Immunol 178(11):7473–7484PubMedGoogle Scholar
- Gomez CR, Boehmer ED, Kovacs EJ et al (2005) The aging innate immune system. Curr Opin Immunol 17(5):457–462PubMedCrossRefGoogle Scholar
- Gruver AL, Hudson LL, Sempowski GD (2007) Immunosenescence of ageing. J Pathol 211(2):144–156. doi: 10.1002/path.2104 PubMedCrossRefGoogle Scholar
- Grzegorzewski K, Komschlies KL, Mori M et al (1994) Administration of recombinant human interleukin-7 to mice induces the exportation of myeloid progenitor cells from the bone marrow to peripheral sites. Blood 83(2):377–385PubMedGoogle Scholar
- Harris JM, Hazenberg MD, Pulin JF et al (2005) Multiparameter evaluation of human thymic function: interpretations and caveats. Clin Immunol 115(2):138–146. doi: 10.1016/j.clim.2004.12.008 PubMedCrossRefGoogle Scholar
- Hazenberg MD, Otto SA, Cohen Stuart JW et al (2000) Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naïve T cell population in HIV-1 infection. Nat Med 6(9):1036–1042. doi: 10.1038/79549 PubMedCrossRefGoogle Scholar
- Jamieson BD, Douek DC, Killian S et al (1999) Generation of functional thymocytes in the human adult. Immunity 10(5):569–575. doi: 10.1016/S1074-7613(00)80056-4 PubMedCrossRefGoogle Scholar
- Jiang Q, Li WQ, Aiello FB et al (2005) Retroviral transduction of IL-7Ralpha into IL-7Ralpha-/- bone marrow progenitors: correction of lymphoid deficiency and induction of neutrophilia. Gene Ther 12(24):1761–1768. doi: 10.1038/sj.gt.3302558 PubMedCrossRefGoogle Scholar
- Kilpatrick RD, Rickabaugh T, Hultin LE et al (2008) Homeostasis of the naïve CD4+ T cell compartment during aging. J Immunol 180(3):1499–1507PubMedGoogle Scholar
- Kumamoto T, Inaba M, Toki J et al (1995) Cytotoxic effects of irradiation and deoxyguanosine on fetal thymus. Immunobiology 192(5):365–381PubMedGoogle Scholar
- Lord JM, Butcher S, Killampali V et al (2001) Neutrophil ageing and immunesenescence. Mech Ageing Dev 122(14):1521–1535. doi: 10.1016/S0047-6374(01)00285-8 PubMedCrossRefGoogle Scholar
- Mackall CL, Fleisher TA, Brown MR et al (1995) Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 332(3):143–149. doi: 10.1056/NEJM199501193320303 PubMedCrossRefGoogle Scholar
- Marinova TT (2005) Epithelial framework reorganization during human thymus involution. Gerontology 51(1):14–18. doi: 10.1159/000081429 PubMedCrossRefGoogle Scholar
- Marusic M, Turkalj-Kljajic M, Petrovecki M et al (1998) Indirect demonstration of the lifetime function of human thymus. Clin Exp Immunol 111(2):450–456. doi: 10.1046/j.1365-2249.1998.00470.x PubMedCrossRefGoogle Scholar
- McCune JM, Loftus R, Schmidt DK et al (1998) High prevalence of thymic tissue in adults with human immunodeficiency virus-1 infection. J Clin Invest 101(11):2299–2300. doi: 10.1172/JCI2834 CrossRefGoogle Scholar
- Pawelec G, Koch S, Gouttefangeas C et al (2006) Immunorejuvenation in the elderly. Rejuvenation Res 9(1):111–116. doi: 10.1089/rej.2006.9.111 PubMedCrossRefGoogle Scholar
- Poulin JF, Viswathan MN, Harris JM et al (1999) Direct evidence for thymic function in adult humans. J Exp Med 190(4):479–486. doi: 10.1084/jem.190.4.479 PubMedCrossRefGoogle Scholar
- Sempowski GD, Hale LP, Sundy JS et al (2000) Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy. J Immunol 164(4):2180–2187PubMedGoogle Scholar
- Sempowski GD, Gooding ME, Liao HX et al (2002) T cell receptor excision circle assessment of thymopoiesis in aging mice. Mol Immunol 38(11):841–848. doi: 10.1016/S0161-5890(01)00122-5 PubMedCrossRefGoogle Scholar
- Shanker A (2004) Is thymus redundant after adulthood? Immunol Lett 91(2-3):79–86. doi: 10.1016/j.imlet.2003.12.012 PubMedCrossRefGoogle Scholar
- Strindhall J, Nilsson BO, Lofgren S et al (2007) No Immune Risk Profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study. Exp Gerontol 42(8):753–761. doi: 10.1016/j.exger.2007.05.001 PubMedCrossRefGoogle Scholar
- Sutherland JS, Goldberg GL, Hammett MV et al (2005) Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 175(4):2741–2753PubMedGoogle Scholar
- Targonski PV, Jacobson RM, Poland GA (2007) Immunosenescence: role and measurement in influenza vaccine response among the elderly. Vaccine 25(16):3066–3069. doi: 10.1016/j.vaccine.2007.01.025 PubMedCrossRefGoogle Scholar
- Yoshikawa TT (2000) Epidemiology and unique aspects of aging and infectious diseases. Clin Infect Dis 30(6):931–933. doi: 10.1086/313792 PubMedCrossRefGoogle Scholar