title: Interleukin-2 (IL-2) receptor gamma chain mutations in X-linked severe combined immunodeficiency disease result in the loss of high-affinity IL-2 receptor binding.
abstract: Interactions of interleukin-2 (IL-2) with its high-affinity, heterotrimeric receptor (IL-2R alpha beta gamma) play a pivotal role in the autocrine pathway of T lymphocyte expansion required in an immune response. Mutations in the IL-2R gamma chain-encoding gene have been found in SCIDX1, a primary immunodeficiency characterized by the absence of T cell and NK cell development. We have investigated six unrelated SCIDX1 patients for molecular abnormalities of the IL-2R gamma gene. A variety of defects were identified, including the absence of transcripts, frame-shift deletions and point mutations within canonical cytokine receptor motifs (conserved cysteines and the "WS" box). The ability of these mutated IL-2R gamma chains to participate in the function of a high-affinity IL-2R complex was examined by radiolabeled IL-2 binding studies using Epstein-Barr virus-transformed B lymphoblastoid cell lines (B-LCL) derived from SCIDX1 patients. Although normal control B-LCL express high-affinity IL-2 binding sites (Kd = 60 pM, 150 sites/cell), B-LCL derived from SCIDX1 patients failed to bind IL-2 under high-affinity conditions. These SCIDX1 mutations confirm the critical role of the IL-2R gamma chain in T cell and NK cell development. In addition, these data provide insight into the structure/function relationship of the IL-2R gamma chain by identifying residues required for the formation of a high-affinity IL-2R complex.
authors.affiliation: INSERM U132, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: J P
authors.initials: JP
authors.lastname: DiSanto
authors.forename: A
authors.initials: A
authors.lastname: Dautry-Varsat
authors.forename: S
authors.initials: S
authors.lastname: Certain
authors.forename: A
authors.initials: A
authors.lastname: Fischer
authors.forename: G
authors.initials: G
authors.lastname: de Saint Basile
mesh_terms: D001483:Base Sequence; D017931:DNA Primers / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation; D012333:RNA, Messenger / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology*; D014960:X Chromosome
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2