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: N Taylor, L Uribe, S Smith, T Jahn, D B Kohn, K Weinberg
• Journal: Blood (Blood) Vol. 87 Issue 8 Pg. 3103-7 (Apr 15 1996) ISSN: 0006-4971 [Print] United States
• PMID: 8605323 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Interleukin-2
• Receptors, Interleukin-2
• Recombinant Fusion Proteins
• Protein-Tyrosine Kinases
• JAK1 protein, human
• JAK3 protein, human
• Janus Kinase 1
• Janus Kinase 3

Topics

• B-Lymphocytes (drug effects, metabolism, pathology)
• Base Sequence
• Cell Line, Transformed
• Genetic Complementation Test
• Genetic Therapy
• Genetic Vectors (genetics)
• Herpesvirus 4, Human
• Humans
• Interleukin-2 (pharmacology)
• Janus Kinase 1
• Janus Kinase 3
• Male
• Molecular Sequence Data
• Phosphorylation
• Protein Processing, Post-Translational
• Protein-Tyrosine Kinases (metabolism)
• Receptors, Interleukin-2 (biosynthesis, genetics, physiology)
• Recombinant Fusion Proteins (metabolism)
• Retroviridae (genetics)
• Severe Combined Immunodeficiency (genetics, pathology, therapy)
• Transfection
• X Chromosome (genetics)