Restoration of thymic development in an Lck-/- thymoma overexpressing ZAP-70

Thymic development is strictly controlled by Src and Syk family protein tyrosine kinases. The major players in this process are Lck and ZAP-70, which regulate critical di erentiation steps of thymopoiesis. Notwithstanding the critical role of Lck and ZAP-70 in thymocyte development as compared to the related kinases Fyn and Syk, a partial functional redundancy between members of the same family of protein tyrosine kinases has emerged from studies on genetically manipulated mouse models. Furthermore, a close functional interplay between Lck and ZAP-70 in intracellular signaling has been shown to occur in thymocytes. Here we present the characterization of a thymoma from an Lck ÿ/ÿ mouse, where the block in thymocyte development is overcome and the transition between the CD4 ÿ CD8 ÿ and CD4+CD8+ stages is fully restored. Determination of the expression levels of Fyn, ZAP-70 and Syk in thymocytes form the Lck ÿ/ÿ thymoma revealed high levels of ZAP-70 overexpression and recovery of a speci®c subset of phosphoproteins as compared to Lck ÿ/ÿ thymocytes. Hence ZAP-70 overexpression in thymocytes is associated with recovery from the developmental arrest caused by the absence of Lck, suggesting a role for ZAP-70 downstream of Lck in the maturation of CD4+CD8+ thymocytes. 7 2000 Elsevier Science Ltd. All rights reserved