S. Hacein‐Bey, G. Basile, J. Lemerle
Dec 1, 1998
X-linked severe combined immunodeficiency (SCID-Xl) is a rare human inherited disorder in which early T and natural killer (NK) lymphocyte development is blocked. The genetic disorder results from mutations in the common γc chain that participates in several cytokine receptors including the interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors. We have shown in a previous report that γc gene transfer into SCID-Xl bone marrow (BM) cells restores efficient NK cell differentiation. In this study, we have focused on the introduction of the γc gene into SCID-Xl hematopoietic stem cells with the goal of obtaining differentiation into mature T cells. For this purpose, we used the in vitro hybrid fetal thymic organ culture (FTOC) system in which a combination of cytokines consisting of stem cell factor (SCF), Flt-3L, IL-7, IL-1, and IL-15 is added concomitantly. In this culture system, CD34 + marrow cells from two SCID-Xl patients were able to mature into double positive CD4 + CD8 + cells and to a lesser degree into CD4 + TCRβ + single positive cells after retroviral-mediated γc gene transfer. In addition, examination of the output cell population at the TCR DJβ1 locus exhibited multiple rearrangements. These results indicate that restoration of the γc/JAK/STAT signaling pathway during the early developmental stages of thymocytes can correct the T-cell differentiation block in SCID-Xl hematopoietic progenitor cells and therefore establishes a basis for further clinical γc gene transfer studies.