Structure-Function Relationships for High and Low-Affinity Interleukin 2 Receptors
Abstract
The original study of interleukin 2 (IL-2) binding to activated lymphocytes by Robb and colleagues1 described a high-affinity receptor-ligand association which fit nicely with the very low levels of IL-2 which promoted cellular proliferation. Later studies, however, demonstrated that the IL-2 receptor actually existed in a number of forms with drastically different affinities for ligand2. Our subsequent research has focused on explaining these differences in molecular terms and relating them to the function of this versatile growth and differentiation factor. Insight into structure-function relationships for the IL-2-receptor system should prove particularly valuable to the design of drugs which can be used to manipulate IL-2-dependent immunological responses.
Keywords
Versatile GrowthPreview
Unable to display preview. Download preview PDF.
References
- 1.R. J. Robb, A. Munck, and K. A. Smith, T cell growth factor receptors: quantitation, specificity, and biological relevance, J. Exp. Med. 154: 1455 (1981).PubMedCrossRefGoogle Scholar
- 2.R. J. Robb, W. C. Greene, and C. M. Rusk, Low and high affinity cellular receptors for interleukin 2: implications for the level of Tac antigen, J. Exp. Med. 16Ó: 1126 (1984).Google Scholar
- 3.R. J. Robb, C. M. Rusk, J. Yodoi, and W. C. Greene, An interleukin 2 binding molecule distinct from the Tac protein: analysis of its role in formation of high-affinity receptors, Proc. Natl. Acad. Sci. USA 84: 2002 (1987).Google Scholar
- 4.M. Sharon, R. D. Klausner, B. R. Cullen, R. Chizzonite, and W. J. Leonard, Novel interleukin 2 receptor subunit detected by crosslinking under high-affinity conditions, Science 234: 859 (1980).CrossRefGoogle Scholar
- 5.M. Tsudo, R. W. Kozak, C. K. Goldman, and T. A. Waldmann, 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 USA 83: 9694 (1986).PubMedCrossRefGoogle Scholar
- 6.K. Teshigawara, H.-M. Wang, K. Kato, and K. A. Smith, Interleukin 2 high-affinity receptor expression requires two distinct binding proteins, J. Exp. Med. 165: 223 (1987).PubMedCrossRefGoogle Scholar
- 7.W. J. Leonard, J. M. Depper, T. Uchiyama, K. A. Smith, T. A. Waldmann, and W. C. Greene, A monoclonal antibody that appears to recognize the receptor for human T cell growth factor, Nature 300: 267 (1982).PubMedCrossRefGoogle Scholar
- 8.M. Hatakeyama, S. Minamoto, T. Uchiyama, R. R. Hardy, G. Yamada, and T. Taniguchi, Reconstitution of functional receptor for human interleukin-2 in mouse cells, Nature 318: 467 (1985).PubMedCrossRefGoogle Scholar
- 9.S. Kondo, A. Shimizu, M. Maeda, Y. Tagaya, J. Yodoi, and T. Honjo, Expression of functional human interleukin 2 receptor in mouse T cells by cDNA transfection, Nature 320: 75 (1986).PubMedCrossRefGoogle Scholar
- 10.S. Kondo, A. Shimizu, Y. Saito, M. Kinoshita, and T. Honjo, Molecular basis for two different affinity states of the interleukin 2 receptor: affinity conversion model, Proc. Natl. Acad. Sci. USA 83: 9026 (1986).PubMedCrossRefGoogle Scholar
- 11.R. J. Robb, Conversion of low-affinity interleukin 2 receptors to a high-affinity state following fusion of cell membranes, Proc. Natl. Acad. Sci. USA 83: 3992 (1986).PubMedCrossRefGoogle Scholar
- 12.M. Fujii, K. Sugamura, K. Sano, M. Nakai, K. Sugita, and Y. Hinuma, High-affinity receptor-mediated internalization and degradation of interleukin 2 in human T cells, J. Exp. Med. 163: 550 (1986).PubMedCrossRefGoogle Scholar
- 13.L.-M. Kuo, C. M. Rusk, and R. J. Robb, 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 (1986).PubMedGoogle Scholar
- 14.M. P. Neeper, L.-M Kuo, M. C. Kiefer, and R. J. Robb, 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 (1987).PubMedGoogle Scholar
- 15.C. M. Rusk, M. P. Neeper, L.-M. Kuo, R. M. Kutny and R. J. Robb, Structure-function relationships for the IL-2 receptor system. V. Structure-activity analysis of modified and truncated forms of the Tac receptor protein. Site-specific mutagenesis of cysteine residues, J. Immunol. in press.Google Scholar
- 16.J. R. Ortaldo, A. T. Mason, J. P. Gerard, L. E. Henderson, W. Farrar, R. F. Hopkins, R. B. Herberman, and H. Rabin, Effects of natural and recombinant IL-2 on regulation of IFN 3d production and natural killer activity: lack of involvement of the Tac antigen for these immunoregulatory effects, J. Immunol. 133: 779 (1984).PubMedGoogle Scholar
- 17.P. Ralph, G. Jeong, K., Welte, R. Mertelsmann, H. Rabin, L. E. Henderson, L. M. Souza, T. C. Boone, and R. J. Robb, Stimulation of immunoglobulin secretion in human B lymphocytes as a direct effect of high concentration of IL-2, J. Immunol. 133: 2442 (1984).PubMedGoogle Scholar
- 18.M. Dukovich, Y. Wano, Le Thi Bich Thuy, P. Katz, B. R. Callen, J. H. Kerhl and W. C. Greene, A second human interleukin 2 binding protein that may be a component of high-affinity interleukin-2 receptors, Nature 327: 518 (1987).PubMedCrossRefGoogle Scholar
- 19.R. J. Robb, and W. C. Greene, Internalization of interleukin 2 is mediated by the beta chain of the high-affinity IL-2 receptor, J. Exp. Med. 165: 1201 (1987).PubMedCrossRefGoogle Scholar
- 20.R. J. Robb, Structure-function relationships for the interleukin 2 receptor. In: Molecular and Cellular Aspects of Inflammation G. Poste and S.T. Cooke, eds., Plenum Press, NY, pp. 97–122 (1988).CrossRefGoogle Scholar