Interleukin‐2 (IL‐2) receptor γ 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.

Female germ line mosaicism as the origin of a unique IL-2 receptor gamma-chain mutation causing X-linked severe combined immunodeficiency.

“…Although the precise nature of the immunologic lesion produced by the duplication of these three amino acids in IL-2Ry has not been determined, two other SCID-affected patients have been reported with point mutations causing amino acid substitutions in the second tryptophan and serine of the WSXWS sequence (22) as shown in Fig. 2.…”

Defective human interleukin 2 receptor gamma chain in an atypical X chromosome-linked severe combined immunodeficiency with peripheral T cells.

“…Fulllength IL-2Ry chain transcripts were PCR amplified from peripheral T-cell cDNA for direct sequence analysis using reverse transcription-PCR as described (20). Genomic sequences were PCR amplified using primers corresponding to the first two exons (forward exon I primer: 5'-AAGCCAT-CATTACCATTCACA-3' and reverse exon II primer: 5'-GTGGAAACGCTGAGGGAGTC-3'), which amplified the intervening first intron.…”

“…Immunofluorescence was performed as described (20) The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.…”

Endocytosis of the Common Cytokine Receptor γcChain

“…Because it is shared by these interleukin receptors, ␥ c has a critical role in lymphocyte differentiation and proliferation. Indeed, patients suffering from X-linked severe combined immunodeficiency have mutations in the gene encoding ␥ c (10,11).…”