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. 1991 Jan 1;173(1):79–87. doi: 10.1084/jem.173.1.79

Peripheral tolerance to alloantigen results from altered regulation of the interleukin 2 pathway

PMCID: PMC2118748  PMID: 1985127

Abstract

Tolerance to alloantigen may be induced in rats by administration of blood followed by transplantation of a renal allograft. The mechanism of this tolerance was investigated by directly analyzing the functional activity of graft-infiltrating cells. We have previously shown cytotoxic T lymphocyte infiltration of, and major histocompatibility complex induction on, grafts of tolerant animals. We now report that cells isolated from the grafts of tolerant rats show a reduced expression of the p55 interleukin 2 receptor (IL-2R) chain on the cell surface compared with that seen on the cells of untreated animals. Scatchard analysis further reveals low expression of high affinity IL- 2R. This is due to reduced transcription of both IL-2R alpha and beta chain mRNAs and results in a reduced ability of cells to proliferate in response to IL-2. Cells isolated from tolerant animals are unable to make biologically active IL-2 in culture, whereas cells from untreated animals make high levels. This is not reflected at the mRNA level as the IL-2 gene is induced in both tolerant and untreated animals to similar levels. The induction of tolerance is abrogated by administration of recombinant IL-2 to animals at the time of transplantation. Thus, we conclude that an altered regulation of the IL- 2 pathway results in tolerance in these alloantigen-treated and transplanted animals.

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Selected References

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  1. Armstrong H. E., Bolton E. M., McMillan I., Spencer S. C., Bradley J. A. Prolonged survival of actively enhanced rat renal allografts despite accelerated cellular infiltration and rapid induction of both class I and class II MHC antigens. J Exp Med. 1987 Mar 1;165(3):891–907. doi: 10.1084/jem.165.3.891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Blackman M. A., Burgert H. G., Gerhard-Burgert H., Woodland D. L., Palmer E., Kappler J. W., Marrack P. A role for clonal inactivation in T cell tolerance to Mls-1a. Nature. 1990 Jun 7;345(6275):540–542. doi: 10.1038/345540a0. [DOI] [PubMed] [Google Scholar]
  3. Bonneville M., Ishida I., Itohara S., Verbeek S., Berns A., Kanagawa O., Haas W., Tonegawa S. Self-tolerance to transgenic gamma delta T cells by intrathymic inactivation. Nature. 1990 Mar 8;344(6262):163–165. doi: 10.1038/344163a0. [DOI] [PubMed] [Google Scholar]
  4. Dallman M. J., Wood K. J., Morris P. J. Specific cytotoxic T cells are found in the nonrejected kidneys of blood-transfused rats. J Exp Med. 1987 Feb 1;165(2):566–571. doi: 10.1084/jem.165.2.566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Eisenberg S. P., Evans R. J., Arend W. P., Verderber E., Brewer M. T., Hannum C. H., Thompson R. C. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature. 1990 Jan 25;343(6256):341–346. doi: 10.1038/343341a0. [DOI] [PubMed] [Google Scholar]
  6. Essery G., Feldmann M., Lamb J. R. Interleukin-2 can prevent and reverse antigen-induced unresponsiveness in cloned human T lymphocytes. Immunology. 1988 Jul;64(3):413–417. [PMC free article] [PubMed] [Google Scholar]
  7. Fabre J. W., Morris P. J. The effect of donor strain blood pretreatment on renal allograft rejection in rats. Transplantation. 1972 Nov;14(5):608–617. doi: 10.1097/00007890-197211000-00013. [DOI] [PubMed] [Google Scholar]
  8. Fiorentino D. F., Bond M. W., Mosmann T. R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. doi: 10.1084/jem.170.6.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fujita T., Takaoka C., Matsui H., Taniguchi T. Structure of the human interleukin 2 gene. Proc Natl Acad Sci U S A. 1983 Dec;80(24):7437–7441. doi: 10.1073/pnas.80.24.7437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fuse A., Fujita T., Yasumitsu H., Kashima N., Hasegawa K., Taniguchi T. Organization and structure of the mouse interleukin-2 gene. Nucleic Acids Res. 1984 Dec 21;12(24):9323–9331. doi: 10.1093/nar/12.24.9323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hannum C. H., Wilcox C. J., Arend W. P., Joslin F. G., Dripps D. J., Heimdal P. L., Armes L. G., Sommer A., Eisenberg S. P., Thompson R. C. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. doi: 10.1038/343336a0. [DOI] [PubMed] [Google Scholar]
  12. Jenkins M. K., Pardoll D. M., Mizuguchi J., Chused T. M., Schwartz R. H. Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5409–5413. doi: 10.1073/pnas.84.15.5409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
  14. Kisielow P., Blüthmann H., Staerz U. D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988 Jun 23;333(6175):742–746. doi: 10.1038/333742a0. [DOI] [PubMed] [Google Scholar]
  15. Ledbetter J. A., Gentry L. E., June C. H., Rabinovitch P. S., Purchio A. F. Stimulation of T cells through the CD3/T-cell receptor complex: role of cytoplasmic calcium, protein kinase C translocation, and phosphorylation of pp60c-src in the activation pathway. Mol Cell Biol. 1987 Feb;7(2):650–656. doi: 10.1128/mcb.7.2.650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ledbetter J. A., Parsons M., Martin P. J., Hansen J. A., Rabinovitch P. S., June C. H. Antibody binding to CD5 (Tp67) and Tp44 T cell surface molecules: effects on cyclic nucleotides, cytoplasmic free calcium, and cAMP-mediated suppression. J Immunol. 1986 Nov 15;137(10):3299–3305. [PubMed] [Google Scholar]
  17. Lindstein T., June C. H., Ledbetter J. A., Stella G., Thompson C. B. Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science. 1989 Apr 21;244(4902):339–343. doi: 10.1126/science.2540528. [DOI] [PubMed] [Google Scholar]
  18. Malkovský M., Medawar P. B., Thatcher D. R., Toy J., Hunt R., Rayfield L. S., Doré C. Acquired immunological tolerance of foreign cells is impaired by recombinant interleukin 2 or vitamin A acetate. Proc Natl Acad Sci U S A. 1985 Jan;82(2):536–538. doi: 10.1073/pnas.82.2.536. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. McKnight A. J., Mason D. W., Barclay A. N. Sequence of rat interleukin 2 and anomalous binding of a mouse interleukin 2 cDNA probe to rat MHC class II-associated invariant chain mRNA. Immunogenetics. 1989;30(2):145–147. doi: 10.1007/BF02421547. [DOI] [PubMed] [Google Scholar]
  20. Morahan G., Allison J., Miller J. F. Tolerance of class I histocompatibility antigens expressed extrathymically. Nature. 1989 Jun 22;339(6226):622–624. doi: 10.1038/339622a0. [DOI] [PubMed] [Google Scholar]
  21. Nossal G. J. Immunologic tolerance: collaboration between antigen and lymphokines. Science. 1989 Jul 14;245(4914):147–153. doi: 10.1126/science.2526369. [DOI] [PubMed] [Google Scholar]
  22. Qin S. X., Cobbold S., Benjamin R., Waldmann H. Induction of classical transplantation tolerance in the adult. J Exp Med. 1989 Mar 1;169(3):779–794. doi: 10.1084/jem.169.3.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ramsdell F., Lantz T., Fowlkes B. J. A nondeletional mechanism of thymic self tolerance. Science. 1989 Nov 24;246(4933):1038–1041. doi: 10.1126/science.2511629. [DOI] [PubMed] [Google Scholar]
  24. Robb R. J., Greene W. C., Rusk C. M. Low and high affinity cellular receptors for interleukin 2. Implications for the level of Tac antigen. J Exp Med. 1984 Oct 1;160(4):1126–1146. doi: 10.1084/jem.160.4.1126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. doi: 10.1126/science.2999980. [DOI] [PubMed] [Google Scholar]
  26. Schwartz R. H. A cell culture model for T lymphocyte clonal anergy. Science. 1990 Jun 15;248(4961):1349–1356. doi: 10.1126/science.2113314. [DOI] [PubMed] [Google Scholar]
  27. Smith K. A., Cantrell D. A. Interleukin 2 regulates its own receptors. Proc Natl Acad Sci U S A. 1985 Feb;82(3):864–868. doi: 10.1073/pnas.82.3.864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Soulillou J. P., Peyronnet P., Le Mauff B., Hourmant M., Olive D., Mawas C., Delaage M., Hirn M., Jacques Y. Prevention of rejection of kidney transplants by monoclonal antibody directed against interleukin 2. Lancet. 1987 Jun 13;1(8546):1339–1342. doi: 10.1016/s0140-6736(87)90648-9. [DOI] [PubMed] [Google Scholar]
  29. Tellides G., Dallman M. J., Morris P. J. Mechanism of action of interleukin-2 receptor (IL-2R) monoclonal antibody (MAb) therapy: target cell depletion or inhibition of function? Transplant Proc. 1989 Feb;21(1 Pt 1):997–998. [PubMed] [Google Scholar]
  30. Tempelis C. H., Hála K., Krömer G., Schauenstein K., Wick G. Failure to alter neonatal transplantation tolerance by the injection of interleukin 2. Transplantation. 1988 Feb;45(2):449–451. doi: 10.1097/00007890-198802000-00041. [DOI] [PubMed] [Google Scholar]
  31. Wood K. J., Hopley A., Dallman M. J., Morris P. J. Lack of correlation between the induction of donor class I and class II major histocompatibility complex antigens and graft rejection. Transplantation. 1988 Apr;45(4):759–767. doi: 10.1097/00007890-198804000-00019. [DOI] [PubMed] [Google Scholar]
  32. Yokota T., Arai N., Lee F., Rennick D., Mosmann T., Arai K. Use of a cDNA expression vector for isolation of mouse interleukin 2 cDNA clones: expression of T-cell growth-factor activity after transfection of monkey cells. Proc Natl Acad Sci U S A. 1985 Jan;82(1):68–72. doi: 10.1073/pnas.82.1.68. [DOI] [PMC free article] [PubMed] [Google Scholar]

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