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Differential Requirements for ZAP-70 in TCR Signaling and T Cell Development¹

Theresa A. Kadlecek^*, Nicolai S. C. van Oers^2,*, Leo Lefrancois^§, Sara Olson^§, Deborah Finlay, David H. Chu^*,, Kari Connolly, Nigel Killeen and Arthur Weiss^3,*,

^* Howard Hughes Medical Institute, Department of Medicine, Department of Dermatology, and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; and ^§ Division of Rheumatology, Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030

The Syk/ZAP-70 family of protein tyrosine kinases is indispensable for normal lymphoid development. Syk is necessary for the development of B cells and epithelial T cells, whereas ZAP-70 is essential for the normal development of T cells and TCR signaling. In this study, we show that although development of the ß lineage was arrested in the thymus, CD3-positive T cells, primarily of the lineage, were present in the lymph nodes of mice lacking ZAP-70. Moreover, in the absence of ZAP-70, dendritic epidermal T cells were fewer in number and of abnormal morphology, and intestinal intraepithelial lymphocytes, normally containing a large proportion of T cells, were markedly reduced. These data suggest that T cells show a variable dependence upon ZAP-70 for their development. Biochemical analyses of thymocytes revealed a lack of basal -chain tyrosine phosphorylation. However, several other substrates were inducibly tyrosine phosphorylated following TCR stimulation. Thus, TCR-mediated signaling in ZAP-70-deficient thymocytes is only partially impaired. These studies suggest that Syk compensates only partially for the loss of ZAP-70, and that there is an absolute requirement of ZAP-70 for ß T cells and epithelial T cells, but not for some T cells in peripheral lymphoid tissues.