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*
The John P. Robarts Research Institute, and Departments of Microbiology and Immunology, and Medicine, University of Western Ontario, London, Ontario, Canada N6A 5K8; and
Genetics Institute Inc., Cambridge, MA 02140
CTLA-4 is a negative regulator of T cell responses. Sequence
analysis of this molecule reveals the presence of two cytoplasmic
tyrosine residues at positions 165 and 182 that are potential Src
homology (SH)-2 domain binding sites. The role of phosphorylation of
these residues in CTLA-4-mediated signaling is unknown. Here, we show
that sole TCR ligation induces 
-associated protein
(ZAP)-70-dependent tyrosine phosphorylation of CTLA-4 that is important
for cell surface retention of this molecule. However, CTLA-4 tyrosine
phosphorylation is not required for down-regulation of T cell
activation following CD3-CTLA-4 coengagement. Specifically, inhibition
of extracellular signal-regulated kinase (ERK) activation and of IL-2
production by CTLA-4-mediated signaling occurs in T cells expressing
mutant CTLA-4 molecules lacking the cytoplasmic tyrosine residues, and
in lck-deficient or ZAP-70-deficient T cells. Therefore,
CTLA-4 function involves interplay between two different levels of
regulation: phosphotyrosine-dependent cell surface retention and
phosphotyrosine-independent association with signaling
molecules.
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