Structure—Function Relations for the Interleukin-2 Receptor

  • Richard J. Robb
Part of the New Horizons in Therapeutics book series (NHTH)


The original study of IL-2 binding to activated lymphocytes (Robb et al., 1981) described a high-affinity receptor—ligand interaction that fit nicely with the extremely low concentrations of IL-2 that were necessary to promote cellular proliferation. Subsequent investigations, however, indicated that the interaction of IL-2 with cells was not so simple. In particular, antibodies to the IL-2 receptor detected far more receptor molecules on the cell surface than high-affinity IL-2 binding sites (Leonard et al.,1982). As IL-2 became more plentiful, the IL-2 binding assays were extended to higher concentrations of ligand, revealing a second class of low-affinity sites (Robb et al.,1984). The latter sites appeared to account for most or all of the discrepancy between the number of receptors detected with antibodies and the original numerical estimates of high-affinity binding sites. The molecular basis for the two affinity classes of receptor, however, remained unclear. Possible explanations included: (1) the high-and low-affinity sites consisted of distinct IL-2 binding molecules; (2) the affinity difference occurred as a result of variable post-translational modifications of a single IL-2-binding molecule; (3) the difference arose from conformational changes in a single receptor protein, perhaps as a result of homodimer formation or association with a second receptor subunit; and (4) the difference was caused by the effect of a second receptor subunit, present in high-affinity binding sites, which partici-pated directly in ligand binding. In the past year, several laboratories have obtained evidence that the last explanation is indeed the basis for the multiple affinities of the IL-2 receptor.


Disulfide Structure Natural Killer Precursor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ashwell, J. D., Robb, R. J., and Malek, T. R., 1986, Proliferation of T lymphocytes in response to interleukin 2 varies with their state of activation, J. Immunol. 137:2572–2578.PubMedGoogle Scholar
  2. Cosman, D., Cerretti, D. P., Larsen, A., Park, L., March, C., Dower, S., Gillis, S., and Urdal, D., 1984, Cloning, sequence and expression of human interleukin-2 receptor, Nature 312:768–771.PubMedCrossRefGoogle Scholar
  3. Dukovich, M., Wano, Y., Katz, P., Callen, B. R., Kerhl, J. H., and Greene, W. C., 1987, A second human interleukin 2 binding protein that may be a component of high-affinity IL-2 receptors, Nature 327: 518–522.PubMedCrossRefGoogle Scholar
  4. Fujii, M., Sugamura, K., Sano, K., Nakai, M., Sugita, K., and Hinuma, Y., 1986, High-affinity receptor-mediated internalization and degradation of interleukin 2 in human T cells, J. Exp. Med. 163:550–562.PubMedCrossRefGoogle Scholar
  5. Greene, W. C., Robb, R. J., Svetlik, P. B., Rusk, C. M., Depper, J. M., and Leonard, W. J., 1985, Stable expression of cDNA encoding the human interleukin 2 receptor in eucaryotic cells, J. Exp. Med. 162:363–368.PubMedCrossRefGoogle Scholar
  6. Hatakeyama, M., Minamoto, S., Uchiyama, T., Hardy, R. R., Yamada, G., and Taniguchi, T., 1985, Reconstitution of functional receptor for human interleukin-2 in mouse cells, Nature 318:467–470.PubMedCrossRefGoogle Scholar
  7. Kondo, S., Shimizu, A., Maeda, M., Tagaya, Y., Yodoi, J., and Honjo, T., 1986a, Expression of functional human interleukin 2 receptor in mouse T cells by cDNA transfection, Nature 320:75–77.CrossRefGoogle Scholar
  8. Kondo, S., Shimizu, A., Saito, Y., Kinoshita, M., and Honjo, T., 1986b, Molecular basis for two different affinity states of the interleukin 2 receptor: Affinity conversion model, Proc. Natl. Acad. Sci. U.S.A. 83:9026–9029.CrossRefGoogle Scholar
  9. Kuo, L.-M., and Robb, R. J., 1986, Structure—function relationships for the IL 2 receptor system. I. Localization of a receptor binding site on IL 2, J. Immunol. 137:1538–1543.PubMedGoogle Scholar
  10. Kuo, L.-M., Rusk, C. M., and Robb, R. J., 1986, Structure—function relationships for the IL 2—receptor system II. Localization of an IL 2 binding site in high-and low-affinity receptors, J. Immunol. 137:1544–1551.PubMedGoogle Scholar
  11. Leonard, W. J., Depper, J. M., Uchiyama, T., Smith, K. A., Waldmann, T. A., and Greene, W. C., 1982, A monoclonal antibody that appears to recognize the receptor for human T cell growth factor, Nature 300:267–269.PubMedCrossRefGoogle Scholar
  12. Leonard, W. J., Depper, J. M., Crabtree, G. R., Rudikoff, S., Pumphrey, J., Robb, R. J., Krönke, M., Svetlik, P. B., Peffer, N. J., Waldmann, T. A., and Greene, W. C., 1984, Molecular cloning and expression of cDNAs for the human interleukin-2 receptor, Nature 311:626–631.PubMedCrossRefGoogle Scholar
  13. Leonard, W. J., Depper, J. M., Kanehisa, M., Krönke, M., Peffer, N. J., Svetlik, P. B., Sullivan, M., and Greene, W. C., 1985, Structure of human interleukin-2 receptor gene, Science 230:633–639.PubMedCrossRefGoogle Scholar
  14. Miller, J., Malek, T. R., Leonard, W. J., Greene, W. C., Shevach, E. M., and Germain, R. N., 1985, Nucleotide sequence and expression of a mouse interleukin 2 receptor cDNA, J. Immunol. 134:4212–4217.PubMedGoogle Scholar
  15. Neeper, M. P., Kuo, L.-M., Kiefer, M. C., and Robb, R. J., 1987, Structure—function relationships for the IL 2—receptor system. III. Tac protein missing amino acids 102–173 (exon 4) is unable to bind IL 2. Detection of spliced protein after L cell transfection, J. Immunol. 138:3532–3538.PubMedGoogle Scholar
  16. Nikaido, T., Shimizu, N., Ishida, N., Sabe, H., Teshigawara, K., Maeda, M., Uchiyama, T., Yodoi, J., and Honjo, T., 1984, Molecular cloning of cDNA encoding human interleukin-2 receptor, Nature 311:631–635.PubMedCrossRefGoogle Scholar
  17. Ortaldo, J. R., Mason, A. T., Gerard, J. P., Henderson, L. E., Farrar, W., Hopkins, R. F., Herberman, R. B., and Rabin, H., 1984, Effects of natural and recombinant IL-2 on regulation of IFN,. production and natural killer activity: Lack of involvement of the Tac antigen for these immunoregulatory effects, J. Immunol. 133:779–783.PubMedGoogle Scholar
  18. Osawa, H., Josimovic-Alasevic, O., and Diamantstein, T., 1986, Interleukin 2 receptors are released by cells in vitro. I. Detection of soluble IL 2 receptors in cell culture supernatants and in the serum of mice by an immunoradiometric assay. Eur. J. Immunol. 16:467–469.PubMedCrossRefGoogle Scholar
  19. Ralph, P., Jeong, G., Welte, K., Mertelsmann, R., Rabin, H., Henderson, L. E., Souza, L. M., Boone, T. C., and Robb, R. J., 1984, Stimulation of immunoglobulin secretion in human B lymphocytes as a direct effect of high concentration of IL-2, J. Immunol. 133:2442–2445.PubMedGoogle Scholar
  20. Reske-Kunz, A. B., Osawa, H., Josimovic-Alasevic, O., Rude, E., and Diamantstein, T., 1987, Soluble interleukin 2 receptors are released by long-term-cultured insulin-specific T cells transiently after contact with antigen, J. Immunol. 138:192–196.PubMedGoogle Scholar
  21. Robb, R. J., 1984, Interleukin 2: The molecule and its function, Immunol. Today 5:203–209CrossRefGoogle Scholar
  22. Robb, R. J., 1985, Human interleukin 2, in: Methods in Enzymology (G. diSabato, J. J. Langone, and H. VanVunakis, eds.), Vol. 116, pp. 493–525, Academic Press, Orlando, FLGoogle Scholar
  23. Robb, R. J., 1986, Conversion of low-affinity interleukin 2 receptors to a high-affinity state following fusion of cell membranes, Proc. Natl. Acad. Sci. U.S.A. 83:3992–3996.PubMedCrossRefGoogle Scholar
  24. Robb, R. J., and Greene, W. C., 1983, Direct demonstration of the identity of T cell growth factor binding protein and the Tac antigen, J. Exp. Med. 158:1332–1337.PubMedCrossRefGoogle Scholar
  25. Robb, R. J., and Greene, W. C., 1987, Internalization of interleukin 2 is mediated by the beta chain of the high-affinity IL-2 receptor, J. Exp. Med. 165:1201–1206.PubMedCrossRefGoogle Scholar
  26. Robb, R. J., and Kutny, R. M., 1987, Structure-function relationships for the IL 2-receptor system, IV. Analysis of the sequence and ligand-binding properties of soluble Tac protein J. Immunol. 139:855–862.PubMedGoogle Scholar
  27. Robb, R. J., and Lin, Y., 1984, T-cell growth factor: Purification, interaction with a cellular receptor, and in vitro synthesis, in: Thymic Hormones and Lymphokines ‘83 (A. L. Goldstein, ed.), pp. 247–256, Plenum Press, New York.Google Scholar
  28. Robb, R. J., and Rusk, C. M., 1986, High and low affinity receptors for interleukin 2: Implications of pronase, phorbol ester, and cell membrane studies upon the basis for differential ligand affinities, J. Immunol. 137:142–149.PubMedGoogle Scholar
  29. Robb, R. J., Munck, A., and Smith, K. A., 1981, T cell growth factor receptors: Quantitation, specificity, and biological relevance. J. Exp. Med. 154:1455–1474.PubMedCrossRefGoogle Scholar
  30. Robb, R. J., Kuntny, R. M., Panico, M., Morris, H. R., DeGrado, W. F., and Chowdhry, V., 1983, Post-translational modification of human T-cell growth factor, Biochem. Biophys. Res. Commun. 116:1049–1055.PubMedCrossRefGoogle Scholar
  31. Robb, R. J., Greene, W. C., and Rusk, C. M., 1984, Low and high affinity cellular receptors for interleukin 2: Implications for the level of Tac antigen, J. Exp. Med. 160:1126–1146.PubMedCrossRefGoogle Scholar
  32. Robb, R. J., Rusk, C. M., Yodoi, J., and Greene, W. C., 1987, An interleukin 2 binding molecule distinct from the Tac protein: Analysis of its role in formation of high-affinity receptors, Proc. Natl. Acad. Sci. U.S.A. 84:2002–2006.PubMedCrossRefGoogle Scholar
  33. Rubin, L. A., Kurman, C. C., Biddison, W. E., Goldman, N. D., and Nelson, D. L., 1985a, A monoclonal antibody, 7G7B6, binds to an epitope on the human interleukin-2 (IL-2) receptor that is distinct from that recognized by IL-2 and anti-Tac, Hybridoma 4:91–102.CrossRefGoogle Scholar
  34. Rubin, L. A., Kurman, C. C., Fritz, M. E., Biddison, W. E., Boutin, B., Yarchoan, R., and Nelson, D. L., 1985b, Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro, J. Immunol. 135:3172–3177.Google Scholar
  35. Rubin, L. A., Jay, G., and Nelson, D. L., 1986, The released interleukin 2 receptor binds interleukin 2 efficiently, J. Immunol. 137:3841–3844.PubMedGoogle Scholar
  36. Shackelford, D. A., and Trowbridge, I. S., 1986, Structural features of the human interleukin-2 receptor, in: Advances in Gene Technology: Molecular Biology of the Endocrine System. (D. Puett, F. Ahmed, S. Black, D. M. Lopez, H. H. Melner, W. A. Scott, and W. J. Whelan, eds.), pp. 390–391, Cambridge University Press, Cambridge, England.Google Scholar
  37. Sharon, M., Klausner, R. D., Cullen, B. R., Chizzonite, R., and Leonard, W. J., 1986, Novel interleukin 2 receptor subunit detected by crosslinking under high-affinity conditions, Science 234:859–864.PubMedCrossRefGoogle Scholar
  38. Teshigawara, K., Wang, H.-M., Kato, K., and Smith, K. A., 1987, Interleukin 2 high-affinity receptor expression requires two distinct binding proteins, J. Exp. Med. 165:223–228.PubMedCrossRefGoogle Scholar
  39. Treiger, B. F., Leonard, W. J., Svetlik, P., Rubin, L. A., Nelson, D. L., and Greene, W. C., 1986, A secreted form of the human interleukin 2 receptor encoded by an “anchor minus” cDNA, J. Immunol. 136:4099–4105.PubMedGoogle Scholar
  40. Tsudo, M., Kozak, R. W., Goldman, C. K., and Waldmann, T. A., 1986, Demonstration of a new non-Tac peptide that binds interleukin 2: A potential participant in a multichain interleukin-2 receptor complex, Proc. Natl. Acad. Sci. U.S.A. 83:9694–9698.PubMedCrossRefGoogle Scholar
  41. Weissman, A. M., Harford, J. B., Svetlik, P. B., Leonard, W. J., Depper, J. M., Waldmann, T. A., Greene, W. C., and Klausner, R. D., 1986, Only high-affinity receptors for interleukin 2 mediate internalization of ligand, Proc. Natl. Acad. Sci. U.S.A. 83:1463–1468.PubMedCrossRefGoogle Scholar
  42. Yodoi, J., Teshigawara, K., Nikaido, T., Fukui, K., Noma, T., Honjo, T., Takigawa, M., Sasaki, M., Minato, N., Tsudo, M., Uchiyama, T., and Maeda, M., 1985, TCGF (IL-2)receptor inducing factor(s). I. Regulation of IL-2 receptor on a natural killer-like cell line (YT cells), J. Immunol. 134:1623–1630.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Richard J. Robb
    • 1
  1. 1.Medical Products Department, Glenolden LaboratoryE. I. du Pont de Nemours & CompanyGlenoldenUSA

Personalised recommendations