Journal of Biomedical Science

, Volume 7, Issue 4, pp 317–321 | Cite as

Age-associated changes in interferon-γ and interleukin-4 secretion by purified human CD4+ and CD8+ T cells

  • Chung-Jen Yen
  • Shuei-Liong Lin
  • Kuo-Tong Huang
  • Rong-Hwa Lin
Original Paper


Aging is associated with a decline in immune function. Interferon-γ (IFN-γ) and interleukin-4 (IL-4), two important immune deviation-related cytokines, are mainly produced by type 1 and type 2 T cells, respectively. To investigate the age-associated changes in the secretion of these two cytokines, 20 elderly and 20 young subjects fulfilling the SENIEUR protocol were enrolled. The ratios of CD4+ to CD8+ T cells were not different between the two age groups. The CD4+ and CD8+ T cells were purified by a magnetic cell sorting system, and then activated by concurrent anti-CD3 and anti-CD28 stimulation. The released cytokines were determined by ELISA. Both the CD4+ and the CD8+ T cells of the elderly individuals secreted a significantly larger amount of IFN-γ after activation. Profound IL-4 production by CD8+ T cells was observed in the older subjects compared with that of the young subjects. These data suggested that age-associated decrease in immunity may be related to an imbalance in the secretion of immune deviation cytokines. The number of IL-4-secreting CD8+ T cells (T cytotoxic 2) rose significantly in the older individuals. Our design also provided a useful way to differentiate the T cell subsets secreting the same cytokine, such as IFN-γ-producing T helper 1 and T cytotoxic 1 cells.

Key Words

Cytokines Immunosenescence Elderly Lymphocyte subset 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Al-Rayes H, Pachas W, Mirza N, Ahern DJ, Gehn RS, Vercelli D. IgE regulation and lymphokine patterns in aging humans. J Allergy Clin Immunol 90:630–636;1992.Google Scholar
  2. 2.
    Altman DG. Practical Statistics for Medical Research. London, Chapman & Hall, 1991.Google Scholar
  3. 3.
    Ben-Yehuda A, Weksler ME. Immune senescence: Mechanisms and clinical implication. Cancer Invest 10:525–531;1992.Google Scholar
  4. 4.
    Candore G, Di Lorenzo G, Melluso M, Cigna D, Colucci AT, Medica MA, Caruso C. IFN-γ, IL-4 and IL-6 in vitro production in old subjects. Autoimmunity 16:275–280;1993.Google Scholar
  5. 5.
    Carter LL, Dutton RW. Type 1 and type 2: A fundamental dichotomy for all T-cell subsets. Curr Opin Immunol 8:336–342;1996.Google Scholar
  6. 6.
    Castle S, Uyemura K, Wong W, Modlin R, Effros R. Evidence of enhanced type 2 immune response and impaired upregulation of a type 1 response in frail elderly nursing home residents. Mech Ageing Dev 94:7–16;1997.Google Scholar
  7. 7.
    Chopra RK, Holbrook NJ, Powers DC, McCoy MT, Adler WH, Nagel JE. IL-2, IL-2 receptor, and IFN-γ synthesis and mRNA expression in PHA and calcium ionophore-stimulated T cells from elderly humans. Clin Immunol Immunopathol 53:297–308;1989.Google Scholar
  8. 8.
    Delafuente JC. Immunosenescence: Clinical and pharmacologic considerations. Med Clin North Am 69:475–486;1985.Google Scholar
  9. 9.
    De Paoli P, Battistin S, Santini GF. Age-related changes in human lymphocyte subsets: Progressive reduction of the CD4CD45R population. Clin Immunol Immunopathol 48:290–296;1988.Google Scholar
  10. 10.
    Dorian B, Garfinkel PE. Stress, immunity and illness: A review. Psychol Med 17:393–407;1987.Google Scholar
  11. 11.
    Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, Monti D, Franceschi C, Paganelli R. Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 23:2375–2378;1993.Google Scholar
  12. 12.
    Fagnoni FF, Vescovini R, Mazzola M, Bologna G, Nigro E, Lavagetto G, Franceschi C, Passeri M, Sansoni P. Expansion of cytolytic CD8+CD28-T cells in healthy ageing people, including centenarians. Immunology 88:501–507;1996.Google Scholar
  13. 13.
    Ferguson FG, Wikby A, Maxson P, Olsson J, Johansson B. Immune parameters in a longitudinal study of a very old population of Swedish people: A comparison between survivors and nonsurvivors. J Gerontol 50A:B378–382;1995.Google Scholar
  14. 14.
    Fietta A, Merlini C, Dos Santos C, Rovida S, Grassi C. Influence of aging on some specific and nonspecific mechanisms of the host defense system in 146 healthy subjects. Gerontology 40:237–245;1994.Google Scholar
  15. 15.
    Gillis S, Kozak R, Durante M, Weksler ME. Immunological studies of aging: Decreased production of and response to T cell growth factor by lymphocytes from aged humans. J Clin Invest 67:937–942;1981.Google Scholar
  16. 16.
    Goodwin JS. Decreased immunity and increased morbidity in the elderly. Nutr Rev 53:S41–46;1995.Google Scholar
  17. 17.
    Jackson RA, Hawa MI, Roshania RD, Sim BM, DiSilvio L, Jaspan JB. Influence of aging on hepatic and peripheral glucose metabolism in humans. Diabetes 37:119–129;1988.Google Scholar
  18. 18.
    Kapsenberg ML, Jansen HM, Bos JD, Wierenga EA. Role of type 1 and type 2 T helper cells in allergic diseases. Curr Opin Immunol 4:788–793;1992.Google Scholar
  19. 19.
    Kubo M, Cinader B. Polymorphism of age-related changes in interleukin production: Differential changes of T helper subpopulations, synthesizing IL-2, IL-3 and IL-4. Eur J Immunol 20:1289–1296;1990.Google Scholar
  20. 20.
    Li Y, Richards D, Noble A, Kemeny DM. Cytokine production by highly purified human CD8+ T cells. Int Arch Allergy Immunol 107:354–355;1995.Google Scholar
  21. 21.
    Ligthart GJ, Corberand JX, Fournier C, Galanaud P, Hijmans W, Kennes B, Mueller-Hermelink HK, Steinmann GG. Admission criteria for immuno-gerontological studies in man: The SENIEUR protocol. Mech Ageing Dev 28:47–55;1984.Google Scholar
  22. 22.
    Ligthart GJ, Schuit HRE, Hijmans W. Subpopulations of mononuclear cells in ageing: Expression of the null cell compartment and disease in the number of T and B cells in human blood. Immunology 55:15–21;1985.Google Scholar
  23. 23.
    Maggi E, Giudizi MG, Biagiotti R, Annunziato F, Manetti R, Piccinni MP, Parronchi P, Sampognaro S, Giannarini L, Zuccati G, Romagnani S. Th2-like CD8+ T cells showing B cell helper function and reduced cytolytic activity in HIV type 1 infection. J Exp Med 180:489–495;1994.Google Scholar
  24. 24.
    Mili F, Flanders WD, Boring JR, Annest JL, Destefano F. The association of race, smoking and smoking cessation to measures of the immune system in middle-aged men. Clin Immunol Immunopathol 59:187–200;1991.Google Scholar
  25. 25.
    Miltenyi S, Muller W, Weichel W, Radbruch A. High gradient magnetic cell separation with MACS. Cytometry 11:231–238;1990.Google Scholar
  26. 26.
    Mosmann TR, Li L, Sad S. Functions of CD8 T-cell subsets secreting different cytokine patterns. Semin Immunol 9:78–92;1997.Google Scholar
  27. 27.
    Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17:138–146;1996.Google Scholar
  28. 28.
    Mu XY, Thoman ML. The age-dependent cytokine production by murine CD8+ T cells as determined by four-color flow cytometry analysis. J Gerontol 54A:B116-B123;1999.Google Scholar
  29. 29.
    Murasko DM, Bernstein ED. Immunology of aging. In: Hazzard WR, Blass JP, Ettinger WH Jr, Halter JB, Oslander JG, eds. Principles of Geriatric Medicine and Gerontology, ed 4. New York McGraw-Hill, 97–116;1999.Google Scholar
  30. 30.
    Nagel JE, Chopra RK, Powers DC, Adler WH. Effect of age on the human high affinity IL-2 receptor of PHA stimulated PBLs. Clin Exp Immunol 75:286–291;1989.Google Scholar
  31. 31.
    Nagel JE, Chres FJ, Pyle RS, Adler WH. Monoclonal antibody analysis of T lymphocyte subsets in young and aged adults. Immunol Commun 12:223–237;1983.Google Scholar
  32. 32.
    Nagelkerken L, Hertogh-Huijbregts A, Dobber R, Drager A. Age-related changes in lymphokine production related to a decreased number of CD45RBhi CD4+ T cells. Eur J Immunol 21:273–281;1991.Google Scholar
  33. 33.
    Os I, Kjeldsen SE, Westheim A, Akesson I, Eide I, Skjoto J, Hjermann I, Leren P. Aging and urinary vasopressin excretion in healthy men. Scand J Urol Nephrol 21:235–239;1987.Google Scholar
  34. 34.
    Pioli C, Pucci S, Barile S, Frasca D, Doria G. Role of mRNA stability in the different patterns of cytokine production by CD4+ cells from young and old mice. Immunology 94:380–387;1998.Google Scholar
  35. 35.
    Rea IM, Stewart M, Campbell P, Alexander HD, Crockard AD, Morris TC. Changes in lymphocyte subsets, IL-2, and IL-2 receptor in old and very old age. Gerontology 42:69–78;1996.Google Scholar
  36. 36.
    Romagnani S. Human Th1 and Th2 subsets: Regulation of differentiation and role in protection and immunopathology. Int Arch Allergy Immunol 98:279–285;1992.Google Scholar
  37. 37.
    Salgame P, Abrams JS, Clayberger C, Goldston H, Convit J, Modlin RL, Bloom BR. Differing lymphokine profiles of functional subsets of human CD4+ and CD8+ T cell clones. Science 254:279–282;1991.Google Scholar
  38. 38.
    Stratton JR, Cerqueira MD, Schwartz RS, Levy WC, Veith RC, Kahn SE, Abrass IB. Differences in cardiovascular responses to isoproterenol in relation to age and exercise training in healthy men. Circulation 86:504–512;1992.Google Scholar
  39. 39.
    Wakikawa A, Utsuyama M, Wakabayashi A, Kitagawa M, Hirokawa K. Age-related alteration of cytokine production profile by T cell subsets in mice: A flow cytometric study. Exp Gerontol 34:231–242;1999.Google Scholar

Copyright information

© National Science Council 2000

Authors and Affiliations

  • Chung-Jen Yen
    • 1
  • Shuei-Liong Lin
    • 1
  • Kuo-Tong Huang
    • 1
  • Rong-Hwa Lin
    • 2
  1. 1.Department of Internal MedicineNational Taiwan University HospitalTaiwan, ROC
  2. 2.Graduate Institute of Immunology College of MedicineNational Taiwan UniversityTaipeiTaiwan (ROC)

Personalised recommendations