Heterodimerization of the IL-2 receptor beta- and gamma-chain cytoplasmic domains is required for signalling

Nature. 1994 May 26;369(6478):330-3. doi: 10.1038/369330a0.

Abstract

The interaction of interleukin-2 (IL-2) and IL-2 receptors critically regulates the T-cell immune response following antigen activation. IL-2 can signal through high or intermediate affinity receptors which contain IL-2R alpha (refs 3, 4) +beta (refs 5-8) +gamma (ref. 9) or beta+gamma chains, respectively. IL-2R gamma is a common gamma chain, gamma c, also shared by the IL-7 (ref. 10) and IL-4 (refs 11, 12) receptors, which when mutated results in X-linked severe combined immunodeficiency. Using chimaeric receptor constructs together with monoclonal or bispecific antibodies we demonstrate here that IL-2 signalling requires ligand-induced extracellular-domain-mediated heterodimerization of the beta- and gamma c-chain cytoplasmic domains. Anti-IL-2R alpha monoclonal antibodies trigger proliferation of cells transfected with chimaeric constructs in which the extracellular domains of IL-2R beta and gamma c are replaced by that of IL-2R alpha. Other experiments using chimaeric constructs indicated that IL-2 binds monomerically and monovalently to IL-2R alpha and that the beta-transmembrane domain is not required for receptor chain interactions. Finally, we provide a method for mapping residues in the gamma c cytoplasmic domain even in cells that constitutively express gamma c.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific
  • Antibodies, Monoclonal
  • Biopolymers
  • Cell Division / immunology
  • Cell Line
  • Cytoplasm / immunology
  • Humans
  • Mice
  • Mutation
  • Receptors, Interleukin-2 / chemistry*
  • Receptors, Interleukin-2 / physiology
  • Recombinant Fusion Proteins
  • Signal Transduction / immunology*
  • Structure-Activity Relationship

Substances

  • Antibodies, Bispecific
  • Antibodies, Monoclonal
  • Biopolymers
  • Receptors, Interleukin-2
  • Recombinant Fusion Proteins