Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1991 Jan 1;173(1):25–36. doi: 10.1084/jem.173.1.25

Differentiation of T cell lymphokine gene expression: the in vitro acquisition of T cell memory

PMCID: PMC2118764  PMID: 1898663

Abstract

A simple in vitro experimental system was devised to reflect the in vivo generation of a T cell anamnestic response so that T cell differentiation could be examined at the level of lymphokine gene expression. Comparison of neonatal and adult T cells revealed that both populations expressed the genes for interleukin 2 (IL-2) and its receptor, but only adult T cells were capable of transcribing mRNAs for IL-3, IL-4, IL-5, IL-6, interferon gamma, and granulocyte/macrophage colony-stimulating factor. However, neonatal T cells could be induced to undergo functional differentiation in vitro, thereby acquiring the capacity to express the lymphokine gene repertoire characteristic for adult T cells. These data suggest that the T cells generated from neonatal blood by a primary stimulation in vitro are functionally indistinguishable from the T cells in adult blood that presumably have undergone primary stimulation in vivo. Therefore, we propose that the term "memory cell" be applied to those T cells that can be identified by their differentiated state of inducible effector-lymphokine gene expression.

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

Selected References

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

  1. Akbar A. N., Terry L., Timms A., Beverley P. C., Janossy G. Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells. J Immunol. 1988 Apr 1;140(7):2171–2178. [PubMed] [Google Scholar]
  2. Andersson B., Skoglund A. C., Rönnholm M., Lindsten T., Lamon E. W., Collisson E. W., Walia A. S. Functional aspects of IgM and IgG Fc receptors on murine T lymphocytes. Immunol Rev. 1981;56:5–50. doi: 10.1111/j.1600-065x.1981.tb01046.x. [DOI] [PubMed] [Google Scholar]
  3. Anegón I., Cuturi M. C., Trinchieri G., Perussia B. Interaction of Fc receptor (CD16) ligands induces transcription of interleukin 2 receptor (CD25) and lymphokine genes and expression of their products in human natural killer cells. J Exp Med. 1988 Feb 1;167(2):452–472. doi: 10.1084/jem.167.2.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berek C., Milstein C. Mutation drift and repertoire shift in the maturation of the immune response. Immunol Rev. 1987 Apr;96:23–41. doi: 10.1111/j.1600-065x.1987.tb00507.x. [DOI] [PubMed] [Google Scholar]
  5. Bertotto A., Gerli R., Lanfrancone L., Crupi S., Arcangeli C., Cernetti C., Spinozzi F., Rambotti P. Activation of cord T lymphocytes. II. Cellular and molecular analysis of the defective response induced by anti-CD3 monoclonal antibody. Cell Immunol. 1990 May;127(2):247–259. doi: 10.1016/0008-8749(90)90130-j. [DOI] [PubMed] [Google Scholar]
  6. Beverley P. C. Is T-cell memory maintained by crossreactive stimulation? Immunol Today. 1990 Jun;11(6):203–205. doi: 10.1016/0167-5699(90)90083-l. [DOI] [PubMed] [Google Scholar]
  7. Brenner C. A., Tam A. W., Nelson P. A., Engleman E. G., Suzuki N., Fry K. E., Larrick J. W. Message amplification phenotyping (MAPPing): a technique to simultaneously measure multiple mRNAs from small numbers of cells. Biotechniques. 1989 Nov-Dec;7(10):1096–1103. [PubMed] [Google Scholar]
  8. Bryson Y. J., Winter H. S., Gard S. E., Fischer T. J., Stiehm E. R. Deficiency of immune interferon production by leukocytes of normal newborns. Cell Immunol. 1980 Sep 15;55(1):191–200. doi: 10.1016/0008-8749(80)90150-1. [DOI] [PubMed] [Google Scholar]
  9. Byrne J. A., Butler J. L., Cooper M. D. Differential activation requirements for virgin and memory T cells. J Immunol. 1988 Nov 15;141(10):3249–3257. [PubMed] [Google Scholar]
  10. Byrne J. A., Butler J. L., Reinherz E. L., Cooper M. D. Virgin and memory T cells have different requirements for activation via the CD2 molecule. Int Immunol. 1989;1(1):29–35. doi: 10.1093/intimm/1.1.29. [DOI] [PubMed] [Google Scholar]
  11. Cerottini J. C., Engers H. D., Macdonald H. R., Brunner T. Generation of cytotoxic T lymphocytes in vitro. I. Response of normal and immune mouse spleen cells in mixed leukocyte cultures. J Exp Med. 1974 Sep 1;140(3):703–717. doi: 10.1084/jem.140.3.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cerottini J. C., MacDonald H. R. The cellular basis of T-cell memory. Annu Rev Immunol. 1989;7:77–89. doi: 10.1146/annurev.iy.07.040189.000453. [DOI] [PubMed] [Google Scholar]
  13. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  14. Clement L. T., Yamashita N., Martin A. M. The functionally distinct subpopulations of human CD4+ helper/inducer T lymphocytes defined by anti-CD45R antibodies derive sequentially from a differentiation pathway that is regulated by activation-dependent post-thymic differentiation. J Immunol. 1988 Sep 1;141(5):1464–1470. [PubMed] [Google Scholar]
  15. Damle N. K., Doyle L. V. Ability of human T lymphocytes to adhere to vascular endothelial cells and to augment endothelial permeability to macromolecules is linked to their state of post-thymic maturation. J Immunol. 1990 Feb 15;144(4):1233–1240. [PubMed] [Google Scholar]
  16. Damle N. K., Doyle L. V., Bender J. R., Bradley E. C. Interleukin 2-activated human lymphocytes exhibit enhanced adhesion to normal vascular endothelial cells and cause their lysis. J Immunol. 1987 Mar 15;138(6):1779–1785. [PubMed] [Google Scholar]
  17. Geppert T. D., Lipsky P. E. Accessory cell independent proliferation of human T4 cells stimulated by immobilized monoclonal antibodies to CD3. J Immunol. 1987 Mar 15;138(6):1660–1666. [PubMed] [Google Scholar]
  18. Gerli R., Bertotto A., Crupi S., Arcangeli C., Marinelli I., Spinozzi F., Cernetti C., Angelella P., Rambotti P. Activation of cord T lymphocytes. I. Evidence for a defective T cell mitogenesis induced through the CD2 molecule. J Immunol. 1989 Apr 15;142(8):2583–2589. [PubMed] [Google Scholar]
  19. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  20. Hafler D. A., Fox D. A., Benjamin D., Weiner H. L. Antigen reactive memory T cells are defined by Ta1. J Immunol. 1986 Jul 15;137(2):414–418. [PubMed] [Google Scholar]
  21. Hayward A. R., Lawton A. R. Induction of plasma cell differentiation of human fetal lymphocytes: evidence for functional immaturity of T and B cells. J Immunol. 1977 Oct;119(4):1213–1217. [PubMed] [Google Scholar]
  22. Horgan K. J., Van Seventer G. A., Shimizu Y., Shaw S. Hyporesponsiveness of "naive" (CD45RA+) human T cells to multiple receptor-mediated stimuli but augmentation of responses by co-stimuli. Eur J Immunol. 1990 May;20(5):1111–1118. doi: 10.1002/eji.1830200525. [DOI] [PubMed] [Google Scholar]
  23. Hoy C. A., Rice G. C., Kovacs M., Schimke R. T. Over-replication of DNA in S phase Chinese hamster ovary cells after DNA synthesis inhibition. J Biol Chem. 1987 Sep 5;262(25):11927–11934. [PubMed] [Google Scholar]
  24. Inaba K., Steinman R. M. Resting and sensitized T lymphocytes exhibit distinct stimulatory (antigen-presenting cell) requirements for growth and lymphokine release. J Exp Med. 1984 Dec 1;160(6):1717–1735. doi: 10.1084/jem.160.6.1717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Janossy G., Bofill M., Rowe D., Muir J., Beverley P. C. The tissue distribution of T lymphocytes expressing different CD45 polypeptides. Immunology. 1989 Apr;66(4):517–525. [PMC free article] [PubMed] [Google Scholar]
  26. Koyasu S., Lawton T., Novick D., Recny M. A., Siliciano R. F., Wallner B. P., Reinherz E. L. Role of interaction of CD2 molecules with lymphocyte function-associated antigen 3 in T-cell recognition of nominal antigen. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2603–2607. doi: 10.1073/pnas.87.7.2603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lewis D. B., Larsen A., Wilson C. B. Reduced interferon-gamma mRNA levels in human neonates. Evidence for an intrinsic T cell deficiency independent of other genes involved in T cell activation. J Exp Med. 1986 Apr 1;163(4):1018–1023. doi: 10.1084/jem.163.4.1018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lewis D. B., Prickett K. S., Larsen A., Grabstein K., Weaver M., Wilson C. B. Restricted production of interleukin 4 by activated human T cells. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9743–9747. doi: 10.1073/pnas.85.24.9743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mackay C. R., Marston W. L., Dudler L. Naive and memory T cells show distinct pathways of lymphocyte recirculation. J Exp Med. 1990 Mar 1;171(3):801–817. doi: 10.1084/jem.171.3.801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Matsuyama T., Anderson P., Daley J. F., Schlossman S., Morimoto C. CD4+CD45R+ cells are preferentially activated through the CD2 pathway. Eur J Immunol. 1988 Sep;18(9):1473–1476. doi: 10.1002/eji.1830180926. [DOI] [PubMed] [Google Scholar]
  31. Miyagawa Y., Sugita K., Komiyama A., Akabane T. Delayed in vitro immunoglobulin production by cord lymphocytes. Pediatrics. 1980 Mar;65(3):497–500. [PubMed] [Google Scholar]
  32. Morimoto C., Letvin N. L., Boyd A. W., Hagan M., Brown H. M., Kornacki M. M., Schlossman S. F. The isolation and characterization of the human helper inducer T cell subset. J Immunol. 1985 Jun;134(6):3762–3769. [PubMed] [Google Scholar]
  33. Morimoto C., Letvin N. L., Distaso J. A., Aldrich W. R., Schlossman S. F. The isolation and characterization of the human suppressor inducer T cell subset. J Immunol. 1985 Mar;134(3):1508–1515. [PubMed] [Google Scholar]
  34. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  35. Mullis K. B., Faloona F. A. Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol. 1987;155:335–350. doi: 10.1016/0076-6879(87)55023-6. [DOI] [PubMed] [Google Scholar]
  36. Paliard X., de Waal Malefijt R., Yssel H., Blanchard D., Chrétien I., Abrams J., de Vries J., Spits H. Simultaneous production of IL-2, IL-4, and IFN-gamma by activated human CD4+ and CD8+ T cell clones. J Immunol. 1988 Aug 1;141(3):849–855. [PubMed] [Google Scholar]
  37. Papadogiannakis N., Johnsen S. A., Olding L. B. Monocyte-regulated hyporesponsiveness of human cord blood lymphocytes to OKT3-monoclonal-antibody-induced mitogenesis. Scand J Immunol. 1986 Jan;23(1):91–99. doi: 10.1111/j.1365-3083.1986.tb01946.x. [DOI] [PubMed] [Google Scholar]
  38. Patel S. S., Duby A. D., Thiele D. L., Lipsky P. E. Phenotypic and functional characterization of human T cell clones. J Immunol. 1988 Dec 1;141(11):3726–3736. [PubMed] [Google Scholar]
  39. Pistoia V., Zupo S., Corcione A., Roncella S., Matera L., Ghio R., Ferrarini M. Production of colony-stimulating activity by human natural killer cells: analysis of the conditions that influence the release and detection of colony-stimulating activity. Blood. 1989 Jul;74(1):156–164. [PubMed] [Google Scholar]
  40. Rappolee D. A., Mark D., Banda M. J., Werb Z. Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping. Science. 1988 Aug 5;241(4866):708–712. doi: 10.1126/science.3041594. [DOI] [PubMed] [Google Scholar]
  41. Rappolee D. A., Werb Z. Secretory products of phagocytes. Curr Opin Immunol. 1988 Sep-Oct;1(1):47–55. doi: 10.1016/0952-7915(88)90050-7. [DOI] [PubMed] [Google Scholar]
  42. Rothstein D. M., Sohen S., Daley J. F., Schlossman S. F., Morimoto C. CD4+CD45RA+ and CD4+CD45RA- T cell subsets in man maintain distinct function and CD45RA expression persists on a subpopulation of CD45RA+ cells after activation with Con A. Cell Immunol. 1990 Sep;129(2):449–467. doi: 10.1016/0008-8749(90)90220-l. [DOI] [PubMed] [Google Scholar]
  43. Salmon M., Kitas G. D., Bacon P. A. Production of lymphokine mRNA by CD45R+ and CD45R- helper T cells from human peripheral blood and by human CD4+ T cell clones. J Immunol. 1989 Aug 1;143(3):907–912. [PubMed] [Google Scholar]
  44. Sanders M. E., Makgoba M. W., June C. H., Young H. A., Shaw S. Enhanced responsiveness of human memory T cells to CD2 and CD3 receptor-mediated activation. Eur J Immunol. 1989 May;19(5):803–808. doi: 10.1002/eji.1830190504. [DOI] [PubMed] [Google Scholar]
  45. Sanders M. E., Makgoba M. W., Sharrow S. O., Stephany D., Springer T. A., Young H. A., Shaw S. Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-gamma production. J Immunol. 1988 Mar 1;140(5):1401–1407. [PubMed] [Google Scholar]
  46. Sanders M. E., Makgoba M. W., Shaw S. Human naive and memory T cells: reinterpretation of helper-inducer and suppressor-inducer subsets. Immunol Today. 1988 Jul-Aug;9(7-8):195–199. doi: 10.1016/0167-5699(88)91212-1. [DOI] [PubMed] [Google Scholar]
  47. Schraven B., Roux M., Hutmacher B., Meuer S. C. Triggering of the alternative pathway of human T cell activation involves members of the T 200 family of glycoproteins. Eur J Immunol. 1989 Feb;19(2):397–403. doi: 10.1002/eji.1830190226. [DOI] [PubMed] [Google Scholar]
  48. Serra H. M., Krowka J. F., Ledbetter J. A., Pilarski L. M. Loss of CD45R (Lp220) represents a post-thymic T cell differentiation event. J Immunol. 1988 Mar 1;140(5):1435–1441. [PubMed] [Google Scholar]
  49. Smith S. H., Brown M. H., Rowe D., Callard R. E., Beverley P. C. Functional subsets of human helper-inducer cells defined by a new monoclonal antibody, UCHL1. Immunology. 1986 May;58(1):63–70. [PMC free article] [PubMed] [Google Scholar]
  50. Taylor S., Bryson Y. J. Impaired production of gamma-interferon by newborn cells in vitro is due to a functionally immature macrophage. J Immunol. 1985 Mar;134(3):1493–1497. [PubMed] [Google Scholar]
  51. Tedder T. F., Clement L. T., Cooper M. D. Human lymphocyte differentiation antigens HB-10 and HB-11. I. Ontogeny of antigen expression. J Immunol. 1985 May;134(5):2983–2988. [PubMed] [Google Scholar]
  52. Tedder T. F., Matsuyama T., Rothstein D., Schlossman S. F., Morimoto C. Human antigen-specific memory T cells express the homing receptor (LAM-1) necessary for lymphocyte recirculation. Eur J Immunol. 1990 Jun;20(6):1351–1355. doi: 10.1002/eji.1830200622. [DOI] [PubMed] [Google Scholar]
  53. Thiele D. L., Kurosaka M., Lipsky P. E. Phenotype of the accessory cell necessary for mitogen-stimulated T and B cell responses in human peripheral blood: delineation by its sensitivity to the lysosomotropic agent, L-leucine methyl ester. J Immunol. 1983 Nov;131(5):2282–2290. [PubMed] [Google Scholar]
  54. Thiele D. L., Lipsky P. E. Modulation of human natural killer cell function by L-leucine methyl ester: monocyte-dependent depletion from human peripheral blood mononuclear cells. J Immunol. 1985 Feb;134(2):786–793. [PubMed] [Google Scholar]
  55. Turka L. A., Ledbetter J. A., Lee K., June C. H., Thompson C. B. CD28 is an inducible T cell surface antigen that transduces a proliferative signal in CD3+ mature thymocytes. J Immunol. 1990 Mar 1;144(5):1646–1653. [PubMed] [Google Scholar]
  56. Wilson C. B., Westall J., Johnston L., Lewis D. B., Dower S. K., Alpert A. R. Decreased production of interferon-gamma by human neonatal cells. Intrinsic and regulatory deficiencies. J Clin Invest. 1986 Mar;77(3):860–867. doi: 10.1172/JCI112383. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES