INDUCTION OF T-CELL DIFFERENTIATION AND LYMPHOMAGENESIS IN THE THYMUSOF MICE WITH SEVERE COMBINED IMMUNE-DEFICIENCY (SCID)

Severe combined immune deficiency (SCID) mice have a defect in their r ecombinase system and cannot productively rearrange their immune recep tor genes, Thus, SCID thymocytes are arrested at the immature ''triple negative'' phase, not expressing CD3, CD4, or CD8 surface markers. Wh ole body irradiation of SCID mice induced maturation of their thymocyt es to the CD4(+)/CD8(+) double positive, CD3(+low) stage of differenti ation, and resulted in the generation of a thymic cortical region on h istologic examination. No mature single positive T cells were detected in the thymus or the periphery. VDI rearrangements of TCR-beta with r estricted clonality were observed in the double positive cells from a given individual. The CD3 complex was expressed on some of these cells , but the cells failed to mobilize intracellular calcium after cross-l inking with CD3 Abs. The double positive cells appeared several weeks after irradiation, persisted for many months in the thymus, and by 6 m o generally developed into metastatic lymphoma. Retroviral activation was undetectable in both the preneoplastic and transformed thymocytes. Thus, it appears that the earliest steps in T cell development can be induced in SCID mice by inducing DNA breaks with radiation. This syst em represents a model of early thymic development, preneoplasia, and n eoplasia.