Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Apr 1;183(4):1587–1602. doi: 10.1084/jem.183.4.1587

Metabolism of Tac (IL2Ralpha): physiology of cell surface shedding and renal catabolism, and suppression of catabolism by antibody binding

PMCID: PMC2192498  PMID: 8666917

Abstract

The interleukin 2 receptor alpha (IL2Ralpha; CD25; Tac) is the prototypic model for soluble receptor studies. It exists in vivo as a transmembrane complete molecule (TM-Tac) on cell surfaces and as a truncated soluble form (sTac; sIL2R alpha). sTac has been used as a serum marker of T cell activation in immune disorders and of tumor burden in Tac-expressing malignancies. In vivo, serum levels of all soluble proteins depend on the balance between production and catabolism, but little is known about the metabolic features of this class of molecules. We have developed a model for Tac metabolism that incorporates new insights in its production and catabolism. Tac was shed from the surface of malignant and activated human T cells with a model half-life (t1/2) of 2-6h, but which was prolonged under certain circumstances. The rate of shedding is first order overall and nonsaturable over a two order of magnitude range of substrate (TM-Tac) expression. Once shed from cells Tac is subject to catabolic activities in the host. In vivo studies in mice showed that 90% of Tac was catabolized by the kidney with a t1/2 of 1 h and a filtration fraction of 0.11 relative to creatinine. The remaining 10% of catabolism was mediated by other tissues with a t1/2 of 10 h. Approximately 1-3% of sTac is excreted intact as proteinuria with the remaining 97-99% catabolized to amino acids. Antibody to the receptor induced a marked delay in sTac catabolism by preventing filtration of the smaller protein through the renal glomerulus and additionally suppressing other nonrenal catabolic mechanisms. A discrepancy between the catabolic rats for Tac and anti-Tac in the same complex was interpreted as a previously unrecognized differential catabolic mechanism, suggesting features of the Brambell hypothesis and immunoglobulin G transport and catabolism, in which the antigen-in-complex in intracellular vesicles is relatively less protected from catabolism than the associated antibody. In light of the pivotal role played by the kidney in sTac catabolism and the impact of administered antibody, the serum concentration of Tac in the settings of renal dysfunction or antibody therapy is not a suitable surrogate of activated T cells or of the body burden of tumor. These results provide parameters for assessing soluble receptor-ligand interactions generally.

Full Text

The Full Text of this article is available as a PDF (1.5 MB).

Selected References

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

  1. Ambrosetti A., Semenzato G., Prior M., Chilosi M., Vinante F., Vincenzi C., Zanotti R., Trentin L., Portuese A., Menestrina F. Serum levels of soluble interleukin-2 receptor in hairy cell leukaemia: a reliable marker of neoplastic bulk. Br J Haematol. 1989 Oct;73(2):181–186. doi: 10.1111/j.1365-2141.1989.tb00250.x. [DOI] [PubMed] [Google Scholar]
  2. Arend W. P. Inhibiting the effects of cytokines in human diseases. Adv Intern Med. 1995;40:365–394. [PubMed] [Google Scholar]
  3. BERSON S. A., YALOW R. S., BAUMAN A., ROTHSCHILD M. A., NEWERLY K. Insulin-I131 metabolism in human subjects: demonstration of insulin binding globulin in the circulation of insulin treated subjects. J Clin Invest. 1956 Feb;35(2):170–190. doi: 10.1172/JCI103262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. BRAMBELL F. W., HEMMINGS W. A., MORRIS I. G. A THEORETICAL MODEL OF GAMMA-GLOBULIN CATABOLISM. Nature. 1964 Sep 26;203:1352–1354. doi: 10.1038/2031352a0. [DOI] [PubMed] [Google Scholar]
  5. Bazil V., Strominger J. L. Shedding as a mechanism of down-modulation of CD14 on stimulated human monocytes. J Immunol. 1991 Sep 1;147(5):1567–1574. [PubMed] [Google Scholar]
  6. Brambell F. W. The transmission of immunity from mother to young and the catabolism of immunoglobulins. Lancet. 1966 Nov 19;2(7473):1087–1093. doi: 10.1016/s0140-6736(66)92190-8. [DOI] [PubMed] [Google Scholar]
  7. Chang A. E., Hyatt C. L., Rosenberg S. A. Systemic administration of recombinant human interleukin-2 in mice. J Biol Response Mod. 1984 Oct;3(5):561–572. [PubMed] [Google Scholar]
  8. Cullen B. R., Podlaski F. J., Peffer N. J., Hosking J. B., Greene W. C. Sequence requirements for ligand binding and cell surface expression of the Tac antigen, a human interleukin-2 receptor. J Biol Chem. 1988 Apr 5;263(10):4900–4906. [PubMed] [Google Scholar]
  9. Dal Canton A., Stanziale R., Corradi A., Andreucci V. E., Migone L. Effects of acute ureteral obstruction on glomerular hemodynamics in rat kidney. Kidney Int. 1977 Dec;12(6):403–411. doi: 10.1038/ki.1977.131. [DOI] [PubMed] [Google Scholar]
  10. Depper J. M., Leonard W. J., Krönke M., Noguchi P. D., Cunningham R. E., Waldmann T. A., Greene W. C. Regulation of interleukin 2 receptor expression: effects of phorbol diester, phospholipase C, and reexposure to lectin or antigen. J Immunol. 1984 Dec;133(6):3054–3061. [PubMed] [Google Scholar]
  11. Ehlers M. R., Riordan J. F. Membrane proteins with soluble counterparts: role of proteolysis in the release of transmembrane proteins. Biochemistry. 1991 Oct 22;30(42):10065–10074. doi: 10.1021/bi00106a001. [DOI] [PubMed] [Google Scholar]
  12. Fernandez-Botran R. Soluble cytokine receptors: their role in immunoregulation. FASEB J. 1991 Aug;5(11):2567–2574. doi: 10.1096/fasebj.5.11.1868981. [DOI] [PubMed] [Google Scholar]
  13. Finkelman F. D., Madden K. B., Morris S. C., Holmes J. M., Boiani N., Katona I. M., Maliszewski C. R. Anti-cytokine antibodies as carrier proteins. Prolongation of in vivo effects of exogenous cytokines by injection of cytokine-anti-cytokine antibody complexes. J Immunol. 1993 Aug 1;151(3):1235–1244. [PubMed] [Google Scholar]
  14. Gearing A. J., Beckett P., Christodoulou M., Churchill M., Clements J., Davidson A. H., Drummond A. H., Galloway W. A., Gilbert R., Gordon J. L. Processing of tumour necrosis factor-alpha precursor by metalloproteinases. Nature. 1994 Aug 18;370(6490):555–557. doi: 10.1038/370555a0. [DOI] [PubMed] [Google Scholar]
  15. Gearing A. J., Newman W. Circulating adhesion molecules in disease. Immunol Today. 1993 Oct;14(10):506–512. doi: 10.1016/0167-5699(93)90267-O. [DOI] [PubMed] [Google Scholar]
  16. Goldenberg D. M., Neville A. M., Carter A. C., Go V. L., Holyoke E. D., Isselbacher K. J., Schein P. S., Schwartz M. CEA (carcinoembryonic antigen): its role as a marker in the management of cancer. J Cancer Res Clin Oncol. 1981;101(3):239–242. doi: 10.1007/BF00410109. [DOI] [PubMed] [Google Scholar]
  17. Greene W. C., Leonard W. J., Depper J. M., Nelson D. L., Waldmann T. A. The human interleukin-2 receptor: normal and abnormal expression in T cells and in leukemias induced by the human T-lymphotropic retroviruses. Ann Intern Med. 1986 Oct;105(4):560–572. doi: 10.7326/0003-4819-105-4-560. [DOI] [PubMed] [Google Scholar]
  18. Greene W. C., Leonard W. J., Depper J. M., Nelson D. L., Waldmann T. A. The human interleukin-2 receptor: normal and abnormal expression in T cells and in leukemias induced by the human T-lymphotropic retroviruses. Ann Intern Med. 1986 Oct;105(4):560–572. doi: 10.7326/0003-4819-105-4-560. [DOI] [PubMed] [Google Scholar]
  19. Harris R. H., Gill J. M. Changes in glomerular filtration rate during complete ureteral obstruction in rats. Kidney Int. 1981 Apr;19(4):603–608. doi: 10.1038/ki.1981.58. [DOI] [PubMed] [Google Scholar]
  20. Harrison D., Phillips J. H., Lanier L. L. Involvement of a metalloprotease in spontaneous and phorbol ester-induced release of natural killer cell-associated Fc gamma RIII (CD16-II). J Immunol. 1991 Nov 15;147(10):3459–3465. [PubMed] [Google Scholar]
  21. Henderson L. A., Baynes J. W., Thorpe S. R. Identification of the sites of IgG catabolism in the rat. Arch Biochem Biophys. 1982 Apr 15;215(1):1–11. doi: 10.1016/0003-9861(82)90272-7. [DOI] [PubMed] [Google Scholar]
  22. Humphrey J. H., Fahey J. L. THE METABOLISM OF NORMAL PLASMA PROTEINS AND GAMMA-MYELOMA PROTEIN IN MICE BEARING PLASMA-CELL TUMORS. J Clin Invest. 1961 Sep;40(9):1696–1705. doi: 10.1172/JCI104392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jacques Y., Le Mauff B., Boeffard F., Godard A., Soulillou J. P. A soluble interleukin 2 receptor produced by a normal alloreactive human T cell clone binds interleukin 2 with low affinity. J Immunol. 1987 Oct 1;139(7):2308–2316. [PubMed] [Google Scholar]
  24. Junghans R. P., Dobbs D., Brechbiel M. W., Mirzadeh S., Raubitschek A. A., Gansow O. A., Waldmann T. A. Pharmacokinetics and bioactivity of 1,4,7,10-tetra-azacylododecane off',N'',N'''-tetraacetic acid (DOTA)-bismuth-conjugated anti-Tac antibody for alpha-emitter (212Bi) therapy. Cancer Res. 1993 Dec 1;53(23):5683–5689. [PubMed] [Google Scholar]
  25. LEWALLEN C. G., BERMAN M., RALL J. E. Studies of iodoalbumin metabolism. I. A mathematical approach to the kinetics. J Clin Invest. 1959 Jan 1;38(1 Pt 1):66–87. doi: 10.1172/JCI103796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lawrence E. C., Holland V. A., Young J. B., Windsor N. T., Brousseau K. P., Noon G. P., Whisennand H. H., Debakey M. E., Nelson D. L. Dynamic changes in soluble interleukin-2 receptor levels after lung or heart-lung transplantation. Am Rev Respir Dis. 1989 Sep;140(3):789–796. doi: 10.1164/ajrccm/140.3.789. [DOI] [PubMed] [Google Scholar]
  27. 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. Molecular cloning and expression of cDNAs for the human interleukin-2 receptor. Nature. 1984 Oct 18;311(5987):626–631. doi: 10.1038/311626a0. [DOI] [PubMed] [Google Scholar]
  28. Leonard W. J., Krönke M., Peffer N. J., Depper J. M., Greene W. C. Interleukin 2 receptor gene expression in normal human T lymphocytes. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6281–6285. doi: 10.1073/pnas.82.18.6281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Letellier M., Nakajima T., Pulido-Cejudo G., Hofstetter H., Delespesse G. Mechanism of formation of human IgE-binding factors (soluble CD23): III. Evidence for a receptor (Fc epsilon RII)-associated proteolytic activity. J Exp Med. 1990 Sep 1;172(3):693–700. doi: 10.1084/jem.172.3.693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Marcon L., Fritz M. E., Kurman C. C., Jensen J. C., Nelson D. L. Soluble Tac peptide is present in the urine of normal individuals and at elevated levels in patients with adult T cell leukaemia (ATL). Clin Exp Immunol. 1988 Jul;73(1):29–33. [PMC free article] [PubMed] [Google Scholar]
  31. Meeker T. C., Lowder J., Maloney D. G., Miller R. A., Thielemans K., Warnke R., Levy R. A clinical trial of anti-idiotype therapy for B cell malignancy. Blood. 1985 Jun;65(6):1349–1363. [PubMed] [Google Scholar]
  32. Miedel M. C., Hulmes J. D., Weber D. V., Bailon P., Pan Y. C. Structural analysis of recombinant soluble human interleukin-2 receptor. Primary structure, assignment of disulfide bonds and core IL-2 binding structure. Biochem Biophys Res Commun. 1988 Jul 15;154(1):372–379. doi: 10.1016/0006-291x(88)90695-x. [DOI] [PubMed] [Google Scholar]
  33. Mogielnicki R. P., Waldmann T. A., Strober W. Renal handling of low molecular weight proteins. I. L-Chain metabolism in experimental renal disease. J Clin Invest. 1971 Apr;50(4):901–909. doi: 10.1172/JCI106562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Morrison T. G. Structure, function, and intracellular processing of paramyxovirus membrane proteins. Virus Res. 1988 May;10(2-3):113–135. doi: 10.1016/0168-1702(88)90010-x. [DOI] [PubMed] [Google Scholar]
  35. Müllberg J., Oberthür W., Lottspeich F., Mehl E., Dittrich E., Graeve L., Heinrich P. C., Rose-John S. The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site. J Immunol. 1994 May 15;152(10):4958–4968. [PubMed] [Google Scholar]
  36. Ochs H. R., Smith T. W. Reversal of advanced digitoxin toxicity and modification of pharmacokinetics by specific antibodies and Fab fragments. J Clin Invest. 1977 Dec;60(6):1303–1313. doi: 10.1172/JCI108889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Robb R. J., Kutny R. M. Structure-function relationships for the IL 2-receptor system. IV. Analysis of the sequence and ligand-binding properties of soluble Tac protein. J Immunol. 1987 Aug 1;139(3):855–862. [PubMed] [Google Scholar]
  38. Rubin L. A., Hoekzema G. S., Nelson D. L., Greene W. C., Jay G. Reconstitution of a functional interleukin 2 receptor in a nonlymphoid cell. J Immunol. 1987 Oct 1;139(7):2355–2360. [PubMed] [Google Scholar]
  39. Rutledge E. A., Root B. J., Lucas J. J., Enns C. A. Elimination of the O-linked glycosylation site at Thr 104 results in the generation of a soluble human-transferrin receptor. Blood. 1994 Jan 15;83(2):580–586. [PubMed] [Google Scholar]
  40. Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., Seiki M. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature. 1994 Jul 7;370(6484):61–65. doi: 10.1038/370061a0. [DOI] [PubMed] [Google Scholar]
  41. Schmid S. L., Fuchs R., Male P., Mellman I. Two distinct subpopulations of endosomes involved in membrane recycling and transport to lysosomes. Cell. 1988 Jan 15;52(1):73–83. doi: 10.1016/0092-8674(88)90532-6. [DOI] [PubMed] [Google Scholar]
  42. Schulz G., Cheresh D. A., Varki N. M., Yu A., Staffileno L. K., Reisfeld R. A. Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients. Cancer Res. 1984 Dec;44(12 Pt 1):5914–5920. [PubMed] [Google Scholar]
  43. Sela B. A., Iliopoulos D., Guerry D., Herlyn D., Koprowski H. Levels of disialogangliosides in sera of melanoma patients monitored by sensitive thin-layer chromatography and immunostaining. J Natl Cancer Inst. 1989 Oct 4;81(19):1489–1492. doi: 10.1093/jnci/81.19.1489. [DOI] [PubMed] [Google Scholar]
  44. Semenzato G., Bambara L. M., Biasi D., Frigo A., Vinante F., Zuppini B., Trentin L., Feruglio C., Chilosi M., Pizzolo G. Increased serum levels of soluble interleukin-2 receptor in patients with systemic lupus erythematosus and rheumatoid arthritis. J Clin Immunol. 1988 Nov;8(6):447–452. doi: 10.1007/BF00916949. [DOI] [PubMed] [Google Scholar]
  45. Sharkey R. M., Goldenberg D. M., Goldenberg H., Lee R. E., Ballance C., Pawlyk D., Varga D., Hansen H. J. Murine monoclonal antibodies against carcinoembryonic antigen: immunological, pharmacokinetic, and targeting properties in humans. Cancer Res. 1990 May 1;50(9):2823–2831. [PubMed] [Google Scholar]
  46. Simpson M. A., Madras P. N., Cornaby A. J., Etienne T., Dempsey R. A., Clowes G. H., Monaco A. P. Sequential determinations of urinary cytology and plasma and urinary lymphokines in the management of renal allograft recipients. Transplantation. 1989 Feb;47(2):218–223. doi: 10.1097/00007890-198902000-00004. [DOI] [PubMed] [Google Scholar]
  47. Story C. M., Mikulska J. E., Simister N. E. A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus. J Exp Med. 1994 Dec 1;180(6):2377–2381. doi: 10.1084/jem.180.6.2377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Uchiyama T., Hori T., Tsudo M., Wano Y., Umadome H., Tamori S., Yodoi J., Maeda M., Sawami H., Uchino H. Interleukin-2 receptor (Tac antigen) expressed on adult T cell leukemia cells. J Clin Invest. 1985 Aug;76(2):446–453. doi: 10.1172/JCI111992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Waldmann T. A., Pastan I. H., Gansow O. A., Junghans R. P. The multichain interleukin-2 receptor: a target for immunotherapy. Ann Intern Med. 1992 Jan 15;116(2):148–160. doi: 10.7326/0003-4819-116-2-148. [DOI] [PubMed] [Google Scholar]
  50. Waldmann T. A., Strober W. Metabolism of immunoglobulins. Prog Allergy. 1969;13:1–110. doi: 10.1159/000385919. [DOI] [PubMed] [Google Scholar]
  51. Waldmann T. A., Strober W., Mogielnicki R. P. The renal handling of low molecular weight proteins. II. Disorders of serum protein catabolism in patients with tubular proteinuria, the nephrotic syndrome, or uremia. J Clin Invest. 1972 Aug;51(8):2162–2174. doi: 10.1172/JCI107023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Wano Y., Uchiyama T., Yodoi J., Uchino H. Biosynthetic processing of human interleukin-2 receptor (Tac antigen). Microbiol Immunol. 1985;29(5):451–466. doi: 10.1111/j.1348-0421.1985.tb00846.x. [DOI] [PubMed] [Google Scholar]
  53. West M. A., Lucocq J. M., Watts C. Antigen processing and class II MHC peptide-loading compartments in human B-lymphoblastoid cells. Nature. 1994 May 12;369(6476):147–151. doi: 10.1038/369147a0. [DOI] [PubMed] [Google Scholar]
  54. Wochner R. D., Strober W., Waldmann T. A. The role of the kidney in the catabolism of Bence Jones proteins and immunoglobulin fragments. J Exp Med. 1967 Aug 1;126(2):207–221. doi: 10.1084/jem.126.2.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Zhang L., Aggarwal B. B. Role of sulfhydryl groups in induction of cell surface down-modulation and shedding of extracellular domain of human TNF receptors in human histiocytic lymphoma U937 cells. J Immunol. 1994 Oct 15;153(8):3745–3754. [PubMed] [Google Scholar]

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

RESOURCES