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The Src-Homology Domain 2-Bearing Protein Tyrosine Phosphatase-1 Inhibits Antigen Receptor-Induced Apoptosis of Activated Peripheral T Cells¹

Jinyi Zhang^*, Ally-Khan Somani^*, Stephen Watt, Gordon B. Mills and Katherine A. Siminovitch^2,*

^* Departments of Immunology, Medicine, and Molecular and Medical Genetics, University of Toronto, The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; and Department of Medicine, M.D. Anderson Cancer Center, University of Texas, Houston, TX

Restimulation of Ag receptors on peripheral T lymphocytes induces tyrosine phosphorylation-based signaling cascades that evoke Fas ligand expression and induction of Fas-mediated programmed cell death. In view of the role for the Src homology domain 2-bearing protein tyrosine phosphatase-1 (SHP-1) in modulating TCR signaling, we investigated the influence of SHP-1 on TCR-mediated apoptosis by assaying the sensitivity of peripheral T cells from SHP-1-deficient viable motheaten (me^v) mice to cell death following TCR restimulation. The results of these studies revealed me^v peripheral T cells to be markedly more sensitive than wild-type cells to induction of cell death following TCR stimulation. By contrast, PMA/ionophore and anti-Fas Ab-induced apoptotic responses were no different in me^v compared with wild-type activated cells. Enhanced apoptosis of TCR-restimulated me^v lymphocytes was associated with marked increases in Fas ligand expression as compared with wild-type cells, but was almost abrogated in both me^v and wild-type cells by Fas-Fc treatment. Thus, the increased sensitivity of me^v T cells to apoptosis following TCR restimulation appears to reflect a TCR-driven phenomenon mediated through up-regulation of Fas-Fas ligand interaction and induction of the Fas signaling cascade. These findings, together with the hyperproliferative responses of me^v peripheral T cells to initial TCR stimulation, indicate that SHP-1 modulation of TCR signaling translates to the inhibition of both T cell proliferation and activation and, as such, is likely to play a pivotal role in regulating the expansion of Ag-stimulated T cells during an immune response.

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