Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Nov 1;184(5):1891–1900. doi: 10.1084/jem.184.5.1891

Antigen-independent changes in naive CD4 T cells with aging

PMCID: PMC2192899  PMID: 8920876

Abstract

In the elderly, a dramatic shift within the CD4+ T cell population occurs, with an increased proportion having a memory phenotype with markedly decreased responsiveness. To determine what aspects of the aged phenotype are dependent upon repeated contact with antigen in the environment, we examined CD4+ cells isolated from TCR Tg mice. There is good evidence that no cross-reacting antigens for the Tg TCR recognizing pigeon cytochrome c are found in the environment of the animal, so that alterations in the Tg CD4+ cells with aging are likely to be due to antigen-independent processes. We found that in aged animals, TCR transgene(pos) CD4+ cells, although decreased in number and antigen responsiveness, maintain a naive phenotype rather than acquiring a prototypical aged memory phenotype. In contrast, the population of transgene(1o-neg) CD4+ cells increase in proportion and express the aged phenotype. Consistent with their naive status, transgene(pos) cells of aged individuals remain CD44lo CD45RBhi, secrete IL-2 and not IL-4 or IFN-gamma upon antigenic stimulation, and require co-stimulation to proliferate to anti-CD3 stimulation. These findings suggest that the aging-associated shift to CD4 cells expressing the memory phenotype is dependent on antigenic stimulation. However, the decrease in antigen responsiveness of naive transgenepos cells, as revealed by a lower secretion of IL-2 and IL-3 and a lower proliferative capacity, suggests that additional intrinsic changes occur with aging that do not depend on encounter with antigen.

Full Text

The Full Text of this article is available as a PDF (823.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akbar A. N., Salmon M., Janossy G. The synergy between naive and memory T cells during activation. Immunol Today. 1991 Jun;12(6):184–188. doi: 10.1016/0167-5699(91)90050-4. [DOI] [PubMed] [Google Scholar]
  2. Balomenos D., Balderas R. S., Mulvany K. P., Kaye J., Kono D. H., Theofilopoulos A. N. Incomplete T cell receptor V beta allelic exclusion and dual V beta-expressing cells. J Immunol. 1995 Oct 1;155(7):3308–3312. [PubMed] [Google Scholar]
  3. Bommhardt U., Cerottini J. C., MacDonald H. R. Heterogeneity in P-glycoprotein (multidrug resistance) activity among murine peripheral T cells: correlation with surface phenotype and effector function. Eur J Immunol. 1994 Dec;24(12):2974–2981. doi: 10.1002/eji.1830241208. [DOI] [PubMed] [Google Scholar]
  4. Bradley L. M., Duncan D. D., Yoshimoto K., Swain S. L. Memory effectors: a potent, IL-4-secreting helper T cell population that develops in vivo after restimulation with antigen. J Immunol. 1993 Apr 15;150(8 Pt 1):3119–3130. [PubMed] [Google Scholar]
  5. Chang M. P., Utsuyama M., Hirokawa K., Makinodan T. Decline in the production of interleukin-3 with age in mice. Cell Immunol. 1988 Aug;115(1):1–12. doi: 10.1016/0008-8749(88)90157-8. [DOI] [PubMed] [Google Scholar]
  6. Croft M. Activation of naive, memory and effector T cells. Curr Opin Immunol. 1994 Jun;6(3):431–437. doi: 10.1016/0952-7915(94)90123-6. [DOI] [PubMed] [Google Scholar]
  7. Croft M., Bradley L. M., Swain S. L. Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J Immunol. 1994 Mar 15;152(6):2675–2685. [PubMed] [Google Scholar]
  8. Croft M., Duncan D. D., Swain S. L. Response of naive antigen-specific CD4+ T cells in vitro: characteristics and antigen-presenting cell requirements. J Exp Med. 1992 Nov 1;176(5):1431–1437. doi: 10.1084/jem.176.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dubey C., Croft M., Swain S. L. Costimulatory requirements of naive CD4+ T cells. ICAM-1 or B7-1 can costimulate naive CD4 T cell activation but both are required for optimum response. J Immunol. 1995 Jul 1;155(1):45–57. [PubMed] [Google Scholar]
  10. Effros R. B., Walford R. L. The effect of age on the antigen-presenting mechanism in limiting dilution precursor cell frequency analysis. Cell Immunol. 1984 Oct 15;88(2):531–539. doi: 10.1016/0008-8749(84)90184-9. [DOI] [PubMed] [Google Scholar]
  11. Engwerda C. R., Handwerger B. S., Fox B. S. Aged T cells are hyporesponsive to costimulation mediated by CD28. J Immunol. 1994 Apr 15;152(8):3740–3747. [PubMed] [Google Scholar]
  12. Ernst D. N., Hobbs M. V., Torbett B. E., Glasebrook A. L., Rehse M. A., Bottomly K., Hayakawa K., Hardy R. R., Weigle W. O. Differences in the expression profiles of CD45RB, Pgp-1, and 3G11 membrane antigens and in the patterns of lymphokine secretion by splenic CD4+ T cells from young and aged mice. J Immunol. 1990 Sep 1;145(5):1295–1302. [PubMed] [Google Scholar]
  13. Ernst D. N., Weigle W. O., Noonan D. J., McQuitty D. N., Hobbs M. V. The age-associated increase in IFN-gamma synthesis by mouse CD8+ T cells correlates with shifts in the frequencies of cell subsets defined by membrane CD44, CD45RB, 3G11, and MEL-14 expression. J Immunol. 1993 Jul 15;151(2):575–587. [PubMed] [Google Scholar]
  14. Flurkey K., Stadecker M., Miller R. A. Memory T lymphocyte hyporesponsiveness to non-cognate stimuli: a key factor in age-related immunodeficiency. Eur J Immunol. 1992 Apr;22(4):931–935. doi: 10.1002/eji.1830220408. [DOI] [PubMed] [Google Scholar]
  15. Gottesman M. M., Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem. 1993;62:385–427. doi: 10.1146/annurev.bi.62.070193.002125. [DOI] [PubMed] [Google Scholar]
  16. Gross J. A., Callas E., Allison J. P. Identification and distribution of the costimulatory receptor CD28 in the mouse. J Immunol. 1992 Jul 15;149(2):380–388. [PubMed] [Google Scholar]
  17. Hayakawa K., Hardy R. R. Murine CD4+ T cell subsets defined. J Exp Med. 1988 Nov 1;168(5):1825–1838. doi: 10.1084/jem.168.5.1825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hayakawa K., Hardy R. R. Phenotypic and functional alteration of CD4+ T cells after antigen stimulation. Resolution of two populations of memory T cells that both secrete interleukin 4. J Exp Med. 1989 Jun 1;169(6):2245–2250. doi: 10.1084/jem.169.6.2245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Heath W. R., Miller J. F. Expression of two alpha chains on the surface of T cells in T cell receptor transgenic mice. J Exp Med. 1993 Nov 1;178(5):1807–1811. doi: 10.1084/jem.178.5.1807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hedrick S. M., Engel I., McElligott D. L., Fink P. J., Hsu M. L., Hansburg D., Matis L. A. Selection of amino acid sequences in the beta chain of the T cell antigen receptor. Science. 1988 Mar 25;239(4847):1541–1544. doi: 10.1126/science.2832942. [DOI] [PubMed] [Google Scholar]
  21. Higgins C. F. ABC transporters: from microorganisms to man. Annu Rev Cell Biol. 1992;8:67–113. doi: 10.1146/annurev.cb.08.110192.000435. [DOI] [PubMed] [Google Scholar]
  22. Hobbs M. V., Weigle W. O., Ernst D. N. Interleukin-10 production by splenic CD4+ cells and cell subsets from young and old mice. Cell Immunol. 1994 Apr 1;154(1):264–272. doi: 10.1006/cimm.1994.1076. [DOI] [PubMed] [Google Scholar]
  23. Jemmerson R., Morrow P. R., Klinman N. R., Paterson Y. Analysis of an evolutionarily conserved antigenic site on mammalian cytochrome c using synthetic peptides. Proc Natl Acad Sci U S A. 1985 Mar;82(5):1508–1512. doi: 10.1073/pnas.82.5.1508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Juranka P. F., Zastawny R. L., Ling V. P-glycoprotein: multidrug-resistance and a superfamily of membrane-associated transport proteins. FASEB J. 1989 Dec;3(14):2583–2592. doi: 10.1096/fasebj.3.14.2574119. [DOI] [PubMed] [Google Scholar]
  25. Kaye J., Hedrick S. M. Analysis of specificity for antigen, Mls, and allogenic MHC by transfer of T-cell receptor alpha- and beta-chain genes. Nature. 1988 Dec 8;336(6199):580–583. doi: 10.1038/336580a0. [DOI] [PubMed] [Google Scholar]
  26. Kirschmann D. A., Murasko D. M. Splenic and inguinal lymph node T cells of aged mice respond differently to polyclonal and antigen-specific stimuli. Cell Immunol. 1992 Feb;139(2):426–437. doi: 10.1016/0008-8749(92)90083-2. [DOI] [PubMed] [Google Scholar]
  27. Kubo M., Cinader B. Polymorphism of age-related changes in interleukin (IL) production: differential changes of T helper subpopulations, synthesizing IL 2, IL 3 and IL 4. Eur J Immunol. 1990 Jun;20(6):1289–1296. doi: 10.1002/eji.1830200614. [DOI] [PubMed] [Google Scholar]
  28. Kuhlman P., Moy V. T., Lollo B. A., Brian A. A. The accessory function of murine intercellular adhesion molecule-1 in T lymphocyte activation. Contributions of adhesion and co-activation. J Immunol. 1991 Mar 15;146(6):1773–1782. [PubMed] [Google Scholar]
  29. Lerner A., Yamada T., Miller R. A. Pgp-1hi T lymphocytes accumulate with age in mice and respond poorly to concanavalin A. Eur J Immunol. 1989 Jun;19(6):977–982. doi: 10.1002/eji.1830190604. [DOI] [PubMed] [Google Scholar]
  30. Luqman M., Bottomly K. Activation requirements for CD4+ T cells differing in CD45R expression. J Immunol. 1992 Oct 1;149(7):2300–2306. [PubMed] [Google Scholar]
  31. McHeyzer-Williams M. G., Davis M. M. Antigen-specific development of primary and memory T cells in vivo. Science. 1995 Apr 7;268(5207):106–111. doi: 10.1126/science.7535476. [DOI] [PubMed] [Google Scholar]
  32. Muralidhar G., Koch S., Haas M., Swain S. L. CD4 T cells in murine acquired immunodeficiency syndrome: polyclonal progression to anergy. J Exp Med. 1992 Jun 1;175(6):1589–1599. doi: 10.1084/jem.175.6.1589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nagelkerken L., Hertogh-Huijbregts A., Dobber R., Dräger A. Age-related changes in lymphokine production related to a decreased number of CD45RBhi CD4+ T cells. Eur J Immunol. 1991 Feb;21(2):273–281. doi: 10.1002/eji.1830210206. [DOI] [PubMed] [Google Scholar]
  34. Negoro S., Hara H., Miyata S., Saiki O., Tanaka T., Yoshizaki K., Igarashi T., Kishimoto S. Mechanisms of age-related decline in antigen-specific T cell proliferative response: IL-2 receptor expression and recombinant IL-2 induced proliferative response of purified Tac-positive T cells. Mech Ageing Dev. 1986 Nov 14;36(3):223–241. doi: 10.1016/0047-6374(86)90089-8. [DOI] [PubMed] [Google Scholar]
  35. Nordin A. A., Collins G. D. Limiting dilution analysis of alloreactive cytotoxic precursor cells in aging mice. J Immunol. 1983 Nov;131(5):2215–2218. [PubMed] [Google Scholar]
  36. Pilarski L. M., Paine D., McElhaney J. E., Cass C. E., Belch A. R. Multidrug transporter P-glycoprotein 170 as a differentiation antigen on normal human lymphocytes and thymocytes: modulation with differentiation stage and during aging. Am J Hematol. 1995 Aug;49(4):323–335. doi: 10.1002/ajh.2830490411. [DOI] [PubMed] [Google Scholar]
  37. Shi J., Miller R. A. Differential tyrosine-specific protein phosphorylation in mouse T lymphocyte subsets. Effect of age. J Immunol. 1993 Jul 15;151(2):730–739. [PubMed] [Google Scholar]
  38. Swain S. L., Bradley L. M., Croft M., Tonkonogy S., Atkins G., Weinberg A. D., Duncan D. D., Hedrick S. M., Dutton R. W., Huston G. Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development. Immunol Rev. 1991 Oct;123:115–144. doi: 10.1111/j.1600-065x.1991.tb00608.x. [DOI] [PubMed] [Google Scholar]
  39. Swain S. L., Croft M., Dubey C., Haynes L., Rogers P., Zhang X., Bradley L. M. From naive to memory T cells. Immunol Rev. 1996 Apr;150:143–167. doi: 10.1111/j.1600-065x.1996.tb00700.x. [DOI] [PubMed] [Google Scholar]
  40. Swain S. L. Generation and in vivo persistence of polarized Th1 and Th2 memory cells. Immunity. 1994 Oct;1(7):543–552. doi: 10.1016/1074-7613(94)90044-2. [DOI] [PubMed] [Google Scholar]
  41. Swain S. L., Weinberg A. D., English M. CD4+ T cell subsets. Lymphokine secretion of memory cells and of effector cells that develop from precursors in vitro. J Immunol. 1990 Mar 1;144(5):1788–1799. [PubMed] [Google Scholar]
  42. Unutmaz D., Pileri P., Abrignani S. Antigen-independent activation of naive and memory resting T cells by a cytokine combination. J Exp Med. 1994 Sep 1;180(3):1159–1164. doi: 10.1084/jem.180.3.1159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Utsuyama M., Hirokawa K., Kurashima C., Fukayama M., Inamatsu T., Suzuki K., Hashimoto W., Sato K. Differential age-change in the numbers of CD4+CD45RA+ and CD4+CD29+ T cell subsets in human peripheral blood. Mech Ageing Dev. 1992 Mar 15;63(1):57–68. doi: 10.1016/0047-6374(92)90016-7. [DOI] [PubMed] [Google Scholar]
  44. Utsuyama M., Varga Z., Fukami K., Homma Y., Takenawa T., Hirokawa K. Influence of age on the signal transduction of T cells in mice. Int Immunol. 1993 Sep;5(9):1177–1182. doi: 10.1093/intimm/5.9.1177. [DOI] [PubMed] [Google Scholar]
  45. Whisler R. L., Grants I. S. Age-related alterations in the activation and expression of phosphotyrosine kinases and protein kinase C (PKC) among human B cells. Mech Ageing Dev. 1993 Oct 1;71(1-2):31–46. doi: 10.1016/0047-6374(93)90033-n. [DOI] [PubMed] [Google Scholar]
  46. Witkowski J. M., Li S. P., Gorgas G., Miller R. A. Extrusion of the P glycoprotein substrate rhodamine-123 distinguishes CD4 memory T cell subsets that differ in IL-2-driven IL-4 production. J Immunol. 1994 Jul 15;153(2):658–665. [PubMed] [Google Scholar]
  47. Witkowski J. M., Miller R. A. Increased function of P-glycoprotein in T lymphocyte subsets of aging mice. J Immunol. 1993 Feb 15;150(4):1296–1306. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES