Heterodimerization of the IL-2 receptor beta- and gamma-chain cytoplasmic domains is required for signalling.
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.
Nakamura
Y
Y
Section on Pulmonary and Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Russell
S M
SM
Mess
S A
SA
Friedmann
M
M
Erdos
M
M
Francois
C
C
Jacques
Y
Y
Adelstein
S
S
Leonard
W J
WJ
D000818:Animals; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D001704:Biopolymers; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D003593:Cytoplasm / Q000276:immunology; D006801:Humans; D051379:Mice; D009154:Mutation; D015375:Receptors, Interleukin-2 / Q000737:chemistry* / Q000502:physiology; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction / Q000276:immunology*; D013329:Structure-Activity Relationship
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D001704:Biopolymers; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins