Retroviral-mediated gene transfer restores IL-12 and IL-23 signaling pathways in T cells from IL-12 receptor β1-deficient patients

Marita Bosticardo, Iren Witte, Claire Fieschi, Francesco Novelli, Jean Laurent Casanova, Fabio Candotti

Research output: Contribution to journalArticlepeer-review

Abstract

Genetic deficiency of human IL-12 receptor β1 chain (IL-12Rβ1) results in increased vulnerability to weakly pathogenic strains of Mycobacteria and Salmonella. This phenotype results from the combined lack of IL-12 and IL-23 signaling as both cytokine receptors share IL-12Rβ1. Such infections can be treated by administration of antibiotics and IFN-γ; however, patients can succumb to infections despite these treatments. Reversion of patients' susceptibility by corrective gene transfer could prevent the infectious episodes, thus providing a beneficial alternative. We therefore evaluated the feasibility of retroviral-mediated gene correction of T cells obtained from patients carrying "null" mutations of IL-12Rβ1. Transduction of the IL-12Rβ1 cDNA restored the expression of IL-12Rβ1 and resulted in the reconstitution of a functional IL-12 signaling pathway, as demonstrated by STAT4 phosphorylation and IFN-γ production. IFN-γ production in response to IL-23 was also corrected after gene transfer. These results indicate that the biological defects of T cells from patients carrying IL-12Rβ1 deficiency can be corrected by gene transfer and form the basis for further development of gene therapy for this disease.

Original languageEnglish
Pages (from-to)895-901
Number of pages7
JournalMolecular Therapy
Volume9
Issue number6
DOIs
Publication statusPublished - Jun 2004

Keywords

  • Cytokine receptors
  • Cytokines
  • Gene therapy
  • Immunodeficiency diseases
  • T lymphocytes

ASJC Scopus subject areas

  • Molecular Biology

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