title: Correction of interleukin-2 receptor function in X-SCID lymphoblastoid cells by retrovirally mediated transfer of the gamma-c gene.
abstract: X-SCID, the most common form of human SCID, is due to mutations in the common gamma chain gene (gamma-c) that encodes an essential component of the cytokine receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15. Activation of the Janus family tyrosine kinases Jak1 and Jak3 is necessary for appropriate signalling through the IL-2 receptor (IL-2R). Neither Jak1 nor Jak3 was phosphorylated after IL-2 stimulation of an Epstein-Barr virus-transformed cell line (LCL) from an X-SCID patient with a gamma-c null mutation. However, we now show that appropriate IL-2R function can be restored in an X-SCID LCL by transduction of a wild-type gamma-c gene. A retroviral vector, G1gamma-cSvNa, was constructed and produced in the PG13 packaging line. Transduced X-SCID LCL expressed the G1gamma-cSvNa transcript. IL-2 stimulation of the transduced cell line resulted in appropriate tyrosine phosphorylation of both Jak1 and Jak3. Thus, retroviral-mediated transduction of normal gamma-c can reconstitute downstream signalling through the IL-2R in X-SCID cell lines, suggesting that gene therapy may be a treatment for this disease.
authors.affiliation: Division of Research Immunology and Bone Marrow Transplantation, Childrens Hospital Los Angeles, California 90027, USA.
authors.forename: N
authors.initials: N
authors.lastname: Taylor
authors.forename: L
authors.initials: L
authors.lastname: Uribe
authors.forename: S
authors.initials: S
authors.lastname: Smith
authors.forename: T
authors.initials: T
authors.lastname: Jahn
authors.forename: D B
authors.initials: DB
authors.lastname: Kohn
authors.forename: K
authors.initials: K
authors.lastname: Weinberg
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001483:Base Sequence; D002461:Cell Line, Transformed; D005816:Genetic Complementation Test; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D004854:Herpesvirus 4, Human; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D008297:Male; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D014162:Transfection; D014960:X Chromosome / Q000235:genetics
chemical_list: D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3