High-affinity CD25-binding IL-2 mutants potently stimulate persistent T cell growth.
We have used directed evolution to construct IL-2 mutants that bind the IL-2 alpha receptor subunit (IL-2Ralpha, CD25) with affinities comparable to that of the IL-15-IL-15 alpha receptor subunit (IL-15Ralpha) interaction. T cells proliferate for up to 6 days following a 30 minute incubation with these IL-2 mutants, which may lead to potential applications for cancer and viral immunotherapy. Several alternative mechanisms have been proposed to explain the contrasting effects of IL-2 and IL-15 on T cell proliferation and death. These IL-2 mutants exhibit T cell growth response-receptor occupancy curves indistinguishable from that for IL-15, suggesting that much of the difference between wild-type IL-2 and IL-15 effects arises simply from their 1000-fold differing affinities for their private alpha receptor subunits.
Rao
Balaji M
BM
Department of Chemical Engineering, Massachusetts Institute of Technology, Building 66-552, 77 Massachusetts Avenue, Cambridge, Massachusetts 01239, USA.
Driver
Ian
I
Lauffenburger
Douglas A
DA
Wittrup
K Dane
KD
D019943:Amino Acid Substitution / Q000235:genetics*; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D019020:Directed Molecular Evolution; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism / Q000502:physiology; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D053645:Interleukin-2 Receptor alpha Subunit; D008213:Lymphocyte Activation / Q000235:genetics; D008934:Mitogens / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D018123:Receptors, Interleukin / Q000378:metabolism; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology
C508024:IL15RA protein, human; C508017:IL2RA protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D008934:Mitogens; D018123:Receptors, Interleukin; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2