The Src-homology domain 2-bearing protein tyrosine phosphatase-1 inhibits antigen receptor-induced apoptosis of activated peripheral T cells

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.