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

Thymic development is strictly controlled by Src and Syk family protein tyr osine kinases. The major players in this process are Lck and ZAP-70, which regulate critical differentiation steps of thymopoiesis. Notwithstanding th e critical role of Lck and ZAP-70 in thymocyte development as compared to t he related kinases Fyn and Syk, a partial functional redundancy between mem bers of the same family of protein tyrosine kinases has emerged from studie s on genetically manipulated mouse models. Furthermore, a dose functional i nterplay between Lck and ZAP-70 in intracellular signaling has been shown t o occur in thymocytes. Here we present the characterization of a thymoma fr om an Lck(-/-) mouse, where the block in thymocyte development is overcome and the transition between the CD4(-)CD8(-) and CD4(+)CD8(+) stages is full y restored. Determination of the expression levels of Fyn, ZAP-70 and Syk i n thymocytes form the Lck(-/-) thymoma revealed high levels of ZAP-70 overe xpression and recovery of a specific subset of phosphoproteins as compared to Lck(-/-) thymocytes. Hence ZAP-70 overexpression in thymocytes is associ ated with recovery from the developmental arrest caused by the absence of L ck, suggesting a role for ZAP-70 downstream of Lck in the maturation of CD4 (+)CD8(+) thymocytes. (C) 2000 Elsevier Science Ltd. All rights reserved.