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An Improved Retroviral Gene Transfer Technique Demonstrates Inhibition of CD4^-CD8^- Thymocyte Development by Kinase-Inactive ZAP-70¹

Takehiko Sugawara^*, Vincenzo Di Bartolo^§, Tadaaki Miyazaki, Hiromitsu Nakauchi^*, Oreste Acuto^§ and Yousuke Takahama^2,*,

^* Department of Immunology and PRESTO Research Project, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan; Department of Immunology, Faculty of Medicine, University of Tokyo, Tokyo, Japan; and ^§ Laboratory of Molecular Immunology, Department of Immunology, Institut Pasteur, Paris, France

ZAP-70 is a Syk family tyrosine kinase that plays an essential role in initiating TCR signals. Deficiency in ZAP-70 causes a defect in the development at CD4⁺CD8⁺ thymocytes due to defective TCR-mediated positive and negative selection. Using a newly devised retrovirus gene transfer and an efficient green fluorescence protein detection technique in fetal thymus organ cultures, the present study shows that forced expression in developing thymocytes of a catalytically inactive mutant of ZAP-70, but not wild-type ZAP-70, inhibits T cell development at the earlier CD4^-CD8^- stage. The ZAP-70 mutant blocked the generation of CD4⁺CD8⁺ thymocytes even in the absence of endogenous ZAP-70. Thus, the present results demonstrate a novel technique for gene transfer into developing T cells and suggest that ZAP-70/Syk family tyrosine kinases are involved in the signals inducing the generation of CD4⁺CD8⁺ thymocytes.

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