Rp. Junghans et Ta. Waldmann, METABOLISM OF TAC (IL2R-ALPHA) - PHYSIOLOGY OF CELL-SURFACE SHEDDING AND RENAL CATABOLISM, AND SUPPRESSION OF CATABOLISM BY ANTIBODY-BINDING, The Journal of experimental medicine, 183(4), 1996, pp. 1587-1602
The interleukin 2 receptor alpha (IL2R alpha; CD25; Tac) is the protot
ypic model For soluble receptor studies. It exists in vivo as a transm
embrane complete molecule (TM-Tac) on cell surfaces and as a truncated
soluble form (sTac; sIL2R alpha). sTac has been used as a serum marke
r of T cell activation in immune disorders and of tumor burden in Tac-
exprsssing malignancies. In vivo, serum levels of all soluble proteins
depend oil the balance between production and catabolism, but little
is known about the metabolic features of this class of molecules. We h
ave developed a model for Tac metabolism that incorporates new insight
s in its production and catabolism. Tac was shed from tile surface of
malignant and activated human T cells with a modal half-life (t(1/2))
of 2-6 h, but which was prolonged under certain circumstances. The rat
e of shedding is first order overall and nonsaturable over a two order
of magnitude range of substrate (TM-Tac) expression. Once shed from c
ells, sTac is subject to catabolic activities in tile host. In vivo st
udies in mice showed that 90% of sTac was catabolized by the kidney wi
th a t(1/2) of 1 h and a filtration fraction of 0.11 relative to creat
inine. The remaining 10% of catabolism was mediated by other tissues w
ith a t(1/2) of 10 h. Approximately 1-3% of sTac is excreted intact as
proteinuria with the remaining 97-99% catabolized to amino acids. Ant
ibody to the receptor induced a marked delay in sTac catabolism by pre
venting filtration of the smaller protein through the renal glomerulus
and additionally suppressing other nonrenal catabolic mechanisms. A d
iscrepancy between the catabolic rates for Tac and anti-Tac in the sam
e complex was interpreted as a previously unrecognized differential ca
tabolic mechanism, suggesting features of the Brambell hypothesis and
immunoglobulin G transport and catabolism, in which the antigen-in-com
plex in intracellular vesicles is relatively less protected from catab
olism than the associated antibody. In light oi the pivotal role playe
d by the kidney in sTac catabolism and the impact of administered anti
body, the serum concentration of Tac in the settings of renal dysfunct
ion or antibody therapy is not a suitable surrogate of activated T cel
ls or of the body burden of tumor. These results provide parameters fo
r assessing soluble receptor-ligand interactions generally.