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J Exp Med. 1996 November 1; 184(5): 1891–1900.
PMCID: PMC2192899

Antigen-independent changes in naive CD4 T cells with aging

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Nordin AA, Collins GD. Limiting dilution analysis of alloreactive cytotoxic precursor cells in aging mice. J Immunol. 1983 Nov;131(5):2215–2218. [PubMed]
  • 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. [PubMed]
  • Ernst DN, Hobbs MV, Torbett BE, Glasebrook AL, Rehse MA, Bottomly K, Hayakawa K, Hardy RR, Weigle WO. 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]
  • 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. [PubMed]
  • Hobbs MV, Weigle WO, Ernst DN. Interleukin-10 production by splenic CD4+ cells and cell subsets from young and old mice. Cell Immunol. 1994 Apr 1;154(1):264–272. [PubMed]
  • Chang MP, 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. [PubMed]
  • Shi J, Miller RA. Differential tyrosine-specific protein phosphorylation in mouse T lymphocyte subsets. Effect of age. J Immunol. 1993 Jul 15;151(2):730–739. [PubMed]
  • Whisler RL, Grants IS. 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. [PubMed]
  • 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. [PubMed]
  • Flurkey K, Stadecker M, Miller RA. Memory T lymphocyte hyporesponsiveness to non-cognate stimuli: a key factor in age-related immunodeficiency. Eur J Immunol. 1992 Apr;22(4):931–935. [PubMed]
  • Kirschmann DA, Murasko DM. 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. [PubMed]
  • Lerner A, Yamada T, Miller RA. Pgp-1hi T lymphocytes accumulate with age in mice and respond poorly to concanavalin A. Eur J Immunol. 1989 Jun;19(6):977–982. [PubMed]
  • 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. [PubMed]
  • Ernst DN, Weigle WO, Noonan DJ, McQuitty DN, Hobbs MV. 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]
  • Engwerda CR, Handwerger BS, Fox BS. Aged T cells are hyporesponsive to costimulation mediated by CD28. J Immunol. 1994 Apr 15;152(8):3740–3747. [PubMed]
  • Hayakawa K, Hardy RR. Murine CD4+ T cell subsets defined. J Exp Med. 1988 Nov 1;168(5):1825–1838. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Hayakawa K, Hardy RR. 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. [PMC free article] [PubMed]
  • Swain SL, Bradley LM, Croft M, Tonkonogy S, Atkins G, Weinberg AD, Duncan DD, Hedrick SM, Dutton RW, Huston G. Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development. Immunol Rev. 1991 Oct;123:115–144. [PubMed]
  • Swain SL, Croft M, Dubey C, Haynes L, Rogers P, Zhang X, Bradley LM. From naive to memory T cells. Immunol Rev. 1996 Apr;150:143–167. [PubMed]
  • Akbar AN, Salmon M, Janossy G. The synergy between naive and memory T cells during activation. Immunol Today. 1991 Jun;12(6):184–188. [PubMed]
  • Luqman M, Bottomly K. Activation requirements for CD4+ T cells differing in CD45R expression. J Immunol. 1992 Oct 1;149(7):2300–2306. [PubMed]
  • Dubey C, Croft M, Swain SL. 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]
  • Muralidhar G, Koch S, Haas M, Swain SL. CD4 T cells in murine acquired immunodeficiency syndrome: polyclonal progression to anergy. J Exp Med. 1992 Jun 1;175(6):1589–1599. [PMC free article] [PubMed]
  • Bradley LM, Duncan DD, Yoshimoto K, Swain SL. 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]
  • Witkowski JM, Miller RA. Increased function of P-glycoprotein in T lymphocyte subsets of aging mice. J Immunol. 1993 Feb 15;150(4):1296–1306. [PubMed]
  • Bommhardt U, Cerottini JC, MacDonald HR. 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. [PubMed]
  • Pilarski LM, Paine D, McElhaney JE, Cass CE, Belch AR. 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. [PubMed]
  • Juranka PF, Zastawny RL, Ling V. P-glycoprotein: multidrug-resistance and a superfamily of membrane-associated transport proteins. FASEB J. 1989 Dec;3(14):2583–2592. [PubMed]
  • Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem. 1993;62:385–427. [PubMed]
  • Witkowski JM, Li SP, Gorgas G, Miller RA. 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]
  • Kaye J, Hedrick SM. 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. [PubMed]
  • Croft M, Duncan DD, Swain SL. 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. [PMC free article] [PubMed]
  • Jemmerson R, Morrow PR, Klinman NR, 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. [PubMed]
  • McHeyzer-Williams MG, Davis MM. Antigen-specific development of primary and memory T cells in vivo. Science. 1995 Apr 7;268(5207):106–111. [PubMed]
  • Hedrick SM, Engel I, McElligott DL, Fink PJ, Hsu ML, Hansburg D, Matis LA. Selection of amino acid sequences in the beta chain of the T cell antigen receptor. Science. 1988 Mar 25;239(4847):1541–1544. [PubMed]
  • Balomenos D, Balderas RS, Mulvany KP, Kaye J, Kono DH, Theofilopoulos AN. Incomplete T cell receptor V beta allelic exclusion and dual V beta-expressing cells. J Immunol. 1995 Oct 1;155(7):3308–3312. [PubMed]
  • Croft M, Bradley LM, Swain SL. 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]
  • Kuhlman P, Moy VT, Lollo BA, Brian AA. 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]
  • Gross JA, Callas E, Allison JP. Identification and distribution of the costimulatory receptor CD28 in the mouse. J Immunol. 1992 Jul 15;149(2):380–388. [PubMed]
  • Swain SL, Weinberg AD, 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]
  • Heath WR, Miller JF. 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. [PMC free article] [PubMed]
  • Croft M. Activation of naive, memory and effector T cells. Curr Opin Immunol. 1994 Jun;6(3):431–437. [PubMed]
  • Swain SL. Generation and in vivo persistence of polarized Th1 and Th2 memory cells. Immunity. 1994 Oct;1(7):543–552. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Higgins CF. ABC transporters: from microorganisms to man. Annu Rev Cell Biol. 1992;8:67–113. [PubMed]
  • Effros RB, Walford RL. 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. [PubMed]

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