Retroviral-mediated gene transfer restores IL-12 and IL-23 signaling pathways in T cells from IL-12 receptor beta1-deficient patients.

Genetic deficiency of human IL-12 receptor beta1 chain (IL-12Rbeta1) 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-12Rbeta1. Such infections can be treated by administration of antibiotics and IFN-gamma; 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-12Rbeta1. Transduction of the IL-12Rbeta1 cDNA restored the expression of IL-12Rbeta1 and resulted in the reconstitution of a functional IL-12 signaling pathway, as demonstrated by STAT4 phosphorylation and IFN-gamma production. IFN-gamma 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-12Rbeta1 deficiency can be corrected by gene transfer and form the basis for further development of gene therapy for this disease.