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Laboratory of Lymphocyte Signaling and Development, Molecular Immunology Program, The Babraham Institute, Cambridge, United Kingdom
The balance between positive and negative signals plays a key role
in determining T cell function. CTL-associated Ag-4 is a surface
receptor that can inhibit T cell responses induced upon stimulation of
the TCR and its CD28 coreceptor. Little is known regarding the
signaling mechanisms elicited by CTLA-4. In this study we analyzed
CTLA-4-mediated inhibition of TCR signaling in primary resting human
CD4+ T cells displaying low, but detectable, CTLA-4 cell
surface expression. CTLA-4 coligation with the TCR resulted in reduced
downstream protein tyrosine phosphorylation of signaling effectors and
a striking inhibition of extracellular signal-regulated kinase 1/2
activation. Analysis of proximal TCR signaling revealed that TCR
-chain phosphorylation and subsequent -associated protein of 70
kDa (ZAP-70) tyrosine kinase recruitment were not significantly
affected by CTLA-4 engagement. However, the association of
p56lck with ZAP-70 was inhibited following
CTLA-4 ligation, correlating with reduced actions of
p56lck in the ZAP-70 immunocomplex. Moreover,
CTLA-4 ligation caused the selective inhibition of CD3-mediated
phosphorylation of the positive regulatory ZAP-70 Y319 site. In
addition, we demonstrate protein tyrosine phosphatase activity
associated with the phosphorylated CTLA-4 cytoplasmic tail. The major
phosphatase activity was attributed to Src homology protein 2
domain-containing tyrosine phosphatase 1, a protein tyrosine
phosphatase that has been shown to be a negative regulator of multiple
signaling pathways in hemopoietic cells. Collectively, our findings
suggest that CTLA-4 can act early during the immune response to
regulate the threshold of T cell activation.
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