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

Interactions of interleukin-2 (IL-2) with its high-affinity, heterotri meric receptor (IL-2R alpha beta gamma) play a pivotal role in the aut ocrine pathway of T lymphocyte expansion required in an immune respons e. 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 SCIDX 1 patients for molecular abnormalities of the IL-2R gamma gene. A vari ety of defects were identified, including the absence of transcripts, frame-shift deletions and point mutations within canonical cytokine re ceptor 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 lin es (B-LCL) derived from SCIDX1 patients. Although normal control B-LCL express high-affinity IL-2 binding sites (K-d = 60 pM, 150 sites/cell ), B-LCL derived from SCIDX1 patients failed to bind IL-2 under high-a ffinity conditions. These SCIDX1 mutations confirm the critical role o f 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 form ation of a high-affinity IL-2R complex.