Abstract: The inventors have identified an autosomal dominant (AD) missense mutation in the RAC2 gene (coding for Ras-related botulinum toxin substrate 2 (RAC2)) in three Severe combined immunodeficiencies (SCID) patients whose clinical presentation overlaps with the RD SCID form but who lack AK2 mutations and deafness. Using biochemical and in vitro differentiation assays, the inventors demonstrated that the RAC2 mutation was closely related to an impairment in cell differentiation capacity and defects in cellular and mitochondrial networks. Taken as a whole, the data demonstrate that a dominant gain-of-function (GOF) mutation in the RAC2 protein's GDP/GTP binding site inhibits HSPC differentiation and leads to a severe AD form of SCID with a clinical presentation of RD. Accordingly, the results prompt to consider that introduction of the identified RAC2 mutein in the hematopoietic lineage would be suitable for inducing full ablation of hematopoiesis.

Abstract: The invention relates to the field of cell therapy and to an in vitro method for generating T-cell progenitors, comprising the step of exposing CD34+ cells in a medium containing a Notch ligand, a soluble domain of the Delta-like ligand 4, joined to an Fc region of a protein IgG, in the presence of a fragment of fibronectin comprising the motifs RGDS and CS-1 and a heparin-binding domain.