High-affinity CD25-binding IL-2 mutants potently stimulate persistent T cell growth

Biochemistry. 2005 Aug 9;44(31):10696-701. doi: 10.1021/bi050436x.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Substitution / genetics*
  • Cell Line
  • Cell Membrane / genetics
  • Cell Membrane / immunology
  • Cell Membrane / metabolism
  • Cell Proliferation*
  • Directed Molecular Evolution
  • Humans
  • Interleukin-15 / metabolism
  • Interleukin-15 / physiology
  • Interleukin-2 / genetics*
  • Interleukin-2 / metabolism*
  • Interleukin-2 / physiology
  • Interleukin-2 Receptor alpha Subunit
  • Lymphocyte Activation / genetics
  • Mitogens / genetics
  • Mitogens / metabolism
  • Mitogens / physiology*
  • Protein Binding / genetics
  • Receptors, Interleukin / metabolism
  • Receptors, Interleukin-15
  • Receptors, Interleukin-2 / metabolism*
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology

Substances

  • IL15RA protein, human
  • IL2RA protein, human
  • Interleukin-15
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Mitogens
  • Receptors, Interleukin
  • Receptors, Interleukin-15
  • Receptors, Interleukin-2