Distinctions in lymphocyte responses to IL-2 and IL-15 reflect differential ligand binding interactions with the IL-2Rbeta chain and suggest differential roles for the IL-2Ralpha and IL-15Ralpha subunits.
More interleukin 15 (IL-15) than IL-2 was needed to generate comparable proliferative responses by phytohaemagglutinin (PHA) blasts and Tf-1beta cells expressing high affinity and intermediate affinity IL-2 receptor (IL-2R) complexes, respectively. The focus of these experiments was to determine the contribution of the shared IL-2 and IL-15 receptor components to these dose-response differences. Some of this difference can be attributed to the role of the IL-2Rbeta chain, in that HuMikbeta1, a monoclonal antibody recognizing the IL-2Rbeta chain, blocks 92.2+/-2.5% (mean+/-SE) of the IL-2 proliferative response by Tf-1beta cells but only inhibits 57.9+/-3.7% of the IL-15 response, indicating that IL-2 and IL-15 may physically utilize the IL-2Rbeta chain differently. Monoclonal antibody 341, which recognizes IL-2Rbeta but does not inhibit IL-2 binding to the IL-2Rbeta chain, blocks 35.4+/-2.3% of IL-15-stimulated proliferation of PHA blasts, while not affecting the IL-2-stimulated proliferation. Finally, although HuMikbeta1 does not inhibit IL-2 responses by PHA blasts bearing high affinity IL-2 receptors, HuMikbeta1 does block IL-15-stimulated proliferation by these same cells bearing high affinity IL-15 receptors (88.5+/-1.6% inhibition). This indicates that the role of IL-15Ralpha in the high affinity IL-15R complex is distinct from that of IL-2Ralpha in the high affinity IL-2R complex. Overall, these studies show that the physical interactions of the IL-2Rbetagammac complex with IL-2 are different than the interactions with IL-15.
Department of Human Oncology, University of Wisconsin, Madison 53792, USA.
J L
JL
de Jong
N L
NL
Farner
P M
PM
Sondel
D000818:Animals; D000911:Antibodies, Monoclonal; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D019409:Interleukin-15 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D008024:Ligands; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008954:Models, Biological; D010835:Phytohemagglutinins / Q000494:pharmacology; D011487:Protein Conformation; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000378:metabolism*
D000911:Antibodies, Monoclonal; C508024:IL15RA protein, human; C508025:Il15ra protein, mouse; D019409:Interleukin-15; D007376:Interleukin-2; D008024:Ligands; D010835:Phytohemagglutinins; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2