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Eur J Immunol. 1996 Dec;26(12):3224-9.

The role of tyrosine phosphorylation and PTP-1C in CTLA-4 signal transduction.

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Department of Molecular and Cellular Biology, Cancer Research Laboratory, University of California, Berkeley 94720, USA.


Recently, there has been increasing interest in the inhibitory regulators of lymphocyte activation, and in particular, the role of CD28 homologue CTLA-4 in the regulation of T cell responses. Interaction of CTLA-4 with B7 ligands inhibits T cell responses, including T cell proliferation and interleukin-2 (IL-2) secretion. The mechanism(s) responsible for CTLA-4 signal transduction are unknown, but it has been suggested that tyrosine phosphorylation is involved. Here we demonstrate that phorbol ester phorbol 12-myrislate 13-acetate (PMA), which increases tyrosine phosphorylation by stimulating protein kinase C and p21ras, can overcome the CTLA-4-mediated inhibition of T cell proliferation. This provides the first functional evidence that tyrosine phosphorylation is involved in CTLA-4 signal transduction. Most interestingly, CTLA-4-mediated inhibition of IL-2 secretion was not influenced by the presence of PMA. Further, we demonstrate that CTLA-4 cross-linking inhibits proliferation and IL-2 secretion of T cells from motheaten mice. These mice lack PTP-1C, a tyrosine phosphatase which mediates in a number of lymphocyte inhibitory responses, indicating that PTP-1C is not essential for CTLA-4 signaling. Collectively, these results demonstrate that regulation of tyrosine phosphorylation plays a pivotal role in CTLA-4 function, and that the inhibition of the transition from G0/G1 to the S phase of the cell cycle and the inhibition of IL-2 secretion require distinct signaling pathways. These experiments provide a useful model system which can be used to elucidate the signaling pathways involved in CTLA-4 function and to understand how CTLA-4, CD28 and Tcell receptor-mediated signals are integrated in T cell responses to antigen.

[Indexed for MEDLINE]

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