Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. 1996 Apr 1; 183(4): 1587–1602.
PMCID: PMC2192498

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


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 (1.5M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Fernandez-Botran R. Soluble cytokine receptors: their role in immunoregulation. FASEB J. 1991 Aug;5(11):2567–2574. [PubMed]
  • Gearing AJ, Newman W. Circulating adhesion molecules in disease. Immunol Today. 1993 Oct;14(10):506–512. [PubMed]
  • Arend WP. Inhibiting the effects of cytokines in human diseases. Adv Intern Med. 1995;40:365–394. [PubMed]
  • Ehlers MR, Riordan JF. Membrane proteins with soluble counterparts: role of proteolysis in the release of transmembrane proteins. Biochemistry. 1991 Oct 22;30(42):10065–10074. [PubMed]
  • Waldmann TA, Pastan IH, Gansow OA, Junghans RP. The multichain interleukin-2 receptor: a target for immunotherapy. Ann Intern Med. 1992 Jan 15;116(2):148–160. [PubMed]
  • Greene WC, Leonard WJ, Depper JM, Nelson DL, Waldmann TA. 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. [PubMed]
  • Robb RJ, Kutny RM. 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]
  • Simpson MA, Madras PN, Cornaby AJ, Etienne T, Dempsey RA, Clowes GH, Monaco AP. Sequential determinations of urinary cytology and plasma and urinary lymphokines in the management of renal allograft recipients. Transplantation. 1989 Feb;47(2):218–223. [PubMed]
  • Lawrence EC, Holland VA, Young JB, Windsor NT, Brousseau KP, Noon GP, Whisennand HH, Debakey ME, Nelson DL. Dynamic changes in soluble interleukin-2 receptor levels after lung or heart-lung transplantation. Am Rev Respir Dis. 1989 Sep;140(3):789–796. [PubMed]
  • Semenzato G, Bambara LM, 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. [PubMed]
  • Marcon L, Fritz ME, Kurman CC, Jensen JC, Nelson DL. 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]
  • Rubin LA, Hoekzema GS, Nelson DL, Greene WC, Jay G. Reconstitution of a functional interleukin 2 receptor in a nonlymphoid cell. J Immunol. 1987 Oct 1;139(7):2355–2360. [PubMed]
  • Ambrosetti A, Semenzato G, Prior M, Chilosi M, Vinante F, Vincenzi C, Zanotti R, Trentin L, Portuese A, Menestrina F, et al. 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. [PubMed]
  • Meeker TC, Lowder J, Maloney DG, Miller RA, 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]
  • Schulz G, Cheresh DA, Varki NM, Yu A, Staffileno LK, Reisfeld RA. Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients. Cancer Res. 1984 Dec;44(12 Pt 1):5914–5920. [PubMed]
  • Sela BA, 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. [PubMed]
  • Sharkey RM, Goldenberg DM, Goldenberg H, Lee RE, Ballance C, Pawlyk D, Varga D, Hansen HJ. Murine monoclonal antibodies against carcinoembryonic antigen: immunological, pharmacokinetic, and targeting properties in humans. Cancer Res. 1990 May 1;50(9):2823–2831. [PubMed]
  • Junghans RP, Dobbs D, Brechbiel MW, Mirzadeh S, Raubitschek AA, Gansow OA, Waldmann TA. 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]
  • Greene WC, Leonard WJ, Depper JM, Nelson DL, Waldmann TA. 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. [PubMed]
  • Jacques Y, Le Mauff B, Boeffard F, Godard A, Soulillou JP. 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]
  • Wochner RD, Strober W, Waldmann TA. 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. [PMC free article] [PubMed]
  • Mogielnicki RP, Waldmann TA, 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. [PMC free article] [PubMed]
  • Chang AE, Hyatt CL, Rosenberg SA. Systemic administration of recombinant human interleukin-2 in mice. J Biol Response Mod. 1984 Oct;3(5):561–572. [PubMed]
  • Depper JM, Leonard WJ, Krönke M, Noguchi PD, Cunningham RE, Waldmann TA, Greene WC. 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]
  • Leonard WJ, Depper JM, Crabtree GR, Rudikoff S, Pumphrey J, Robb RJ, Krönke M, Svetlik PB, Peffer NJ, Waldmann TA, et al. Molecular cloning and expression of cDNAs for the human interleukin-2 receptor. Nature. 1984 Oct 18;311(5987):626–631. [PubMed]
  • Leonard WJ, Krönke M, Peffer NJ, Depper JM, Greene WC. Interleukin 2 receptor gene expression in normal human T lymphocytes. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6281–6285. [PMC free article] [PubMed]
  • Cullen BR, Podlaski FJ, Peffer NJ, Hosking JB, Greene WC. 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]
  • 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. [PMC free article] [PubMed]
  • Waldmann TA, Strober W. Metabolism of immunoglobulins. Prog Allergy. 1969;13:1–110. [PubMed]
  • Waldmann TA, Strober W, Mogielnicki RP. 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. [PMC free article] [PubMed]
  • Dal Canton A, Stanziale R, Corradi A, Andreucci VE, Migone L. Effects of acute ureteral obstruction on glomerular hemodynamics in rat kidney. Kidney Int. 1977 Dec;12(6):403–411. [PubMed]
  • Harris RH, Gill JM. Changes in glomerular filtration rate during complete ureteral obstruction in rats. Kidney Int. 1981 Apr;19(4):603–608. [PubMed]
  • LEWALLEN CG, BERMAN M, RALL JE. Studies of iodoalbumin metabolism. I. A mathematical approach to the kinetics. J Clin Invest. 1959 Jan 1;38(1 Pt 1):66–87. [PMC free article] [PubMed]
  • Harrison D, Phillips JH, Lanier LL. 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]
  • Gearing AJ, Beckett P, Christodoulou M, Churchill M, Clements J, Davidson AH, Drummond AH, Galloway WA, Gilbert R, Gordon JL, et al. Processing of tumour necrosis factor-alpha precursor by metalloproteinases. Nature. 1994 Aug 18;370(6490):555–557. [PubMed]
  • Müllberg J, Oberthür W, Lottspeich F, Mehl E, Dittrich E, Graeve L, Heinrich PC, 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]
  • Zhang L, Aggarwal BB. 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]
  • Bazil V, Strominger JL. Shedding as a mechanism of down-modulation of CD14 on stimulated human monocytes. J Immunol. 1991 Sep 1;147(5):1567–1574. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Morrison TG. Structure, function, and intracellular processing of paramyxovirus membrane proteins. Virus Res. 1988 May;10(2-3):113–135. [PubMed]
  • Rutledge EA, Root BJ, Lucas JJ, Enns CA. 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]
  • Miedel MC, Hulmes JD, Weber DV, Bailon P, Pan YC. 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. [PubMed]
  • Wano Y, Uchiyama T, Yodoi J, Uchino H. Biosynthetic processing of human interleukin-2 receptor (Tac antigen). Microbiol Immunol. 1985;29(5):451–466. [PubMed]
  • 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. [PubMed]
  • Ochs HR, Smith TW. Reversal of advanced digitoxin toxicity and modification of pharmacokinetics by specific antibodies and Fab fragments. J Clin Invest. 1977 Dec;60(6):1303–1313. [PMC free article] [PubMed]
  • BERSON SA, YALOW RS, BAUMAN A, ROTHSCHILD MA, 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. [PMC free article] [PubMed]
  • Brambell FW. The transmission of immunity from mother to young and the catabolism of immunoglobulins. Lancet. 1966 Nov 19;2(7473):1087–1093. [PubMed]
  • Schmid SL, 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. [PubMed]
  • Story CM, Mikulska JE, Simister NE. 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. [PMC free article] [PubMed]
  • West MA, Lucocq JM, Watts C. Antigen processing and class II MHC peptide-loading compartments in human B-lymphoblastoid cells. Nature. 1994 May 12;369(6476):147–151. [PubMed]
  • Henderson LA, Baynes JW, Thorpe SR. Identification of the sites of IgG catabolism in the rat. Arch Biochem Biophys. 1982 Apr 15;215(1):1–11. [PubMed]
  • Finkelman FD, Madden KB, Morris SC, Holmes JM, Boiani N, Katona IM, Maliszewski CR. 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]
  • Goldenberg DM, Neville AM, Carter AC, Go VL, Holyoke ED, Isselbacher KJ, Schein PS, 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. [PubMed]

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


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem chemical substance records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records.

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...