The role of low-affinity interleukin-2 receptors in autocrine ligand binding: alternative mechanisms for enhanced binding effect.
T-cell proliferation is regulated by the autocrine ligand interleukin-2 (IL-2), for which these cells possess dual, low-affinity and high-affinity receptor populations. Proliferation stimulated by IL-2 is dependent upon ligand binding to p75, a component of the high-affinity receptor. As with other cells exhibiting dual receptor systems, a central question is, therefore: what is the role of the low-affinity receptor population? We apply a mathematical modeling approach to examine three alternative mechanisms that have been suggested for the role of low-affinity receptors: a ligand reservoir, a receptor reservoir, and a ligand carrier. Using model parameter values specific to the IL-2/T-cell system, we find that only the ligand carrier mechanism leads to binding of autocrine ligand to high-affinity receptors that is increased over levels found on a single, pre-formed high-affinity receptor population. With the ligand reservoir and the receptor reservoir mechanisms, the presence of the low-affinity receptors actually diminishes high-affinity receptor binding due to competition. In contrast, excess low-affinity receptors can act to enhance the level of high-affinity receptor complexes when membrane transport is included, indicating that should this mechanism be inhibited, cell response could potentially be reduced or eliminated. The ligand carrier effect is especially significant for cells expressing a large number (> 10(5) receptors/cell) low-affinity receptors, and at low cell densities (< 10(4) cells/ml). This may at least partially account for the behavior demonstrated by early phase adult T-cell leukemia cells.
Forsten
K E
KE
Department of Chemical Engineering, University of Illinois at Urbana-Champaign 61801.
Lauffenburger
D A
DA
D001692:Biological Transport / Q000502:physiology; D007376:Interleukin-2 / Q000378:metabolism*; D008024:Ligands; D008954:Models, Biological; D011485:Protein Binding; D015375:Receptors, Interleukin-2 / Q000378:metabolism*
D007376:Interleukin-2; D008024:Ligands; D015375:Receptors, Interleukin-2