THE PHOSPHOTYROSINE PHOSPHATASE INHIBITOR PHENYLARSINE OXIDE RESTORESDEFECTIVE PHOSPHOINOSITIDE HYDROLYSIS RESPONSE IN ANERGIC C3H-GLD GLDLYMPHOCYTES/

Mice homozygous for the gld (generalized lymphoproliferative disease) mutation develop both lymphadenopathy and autoimmune disease. CD4(-)CD 8(-) (double negative, DN) T cells comprise the major population of T cells in mature C3H-gld/gld peripheral lymphoid tissues. These DN T ce lls are unresponsive to many forms of stimuli and have previously been shown to exhibit abnormally elevated levels of membrane phosphotyrosi ne phosphatase (PTPase) activity. In the present study, we demonstrate that IP3 production in response to mitogenic stimulation with Con A o r anti-CD3 mAb (145-2C11) is significantly diminished in C3H-gld/gld l ymphocytes when compared to that in congenic C3H-+/+ cells. The capaci ty to produce this second-messenger can be restored by pretreating C3H -gld/gld cells with the PTPase inhibitor, phenylarsine oxide (PAO). Al though the inhibition of PTPase activity by treatment with PAO did res tore C3H-gld/gld cell ability to produce IP3, the signal did not lead to lymphocyte proliferation, but instead to cell death. Our results su ggest that the altered phosphoinositide hydrolysis observed in the mut ant cells is related to their elevated membrane PTPase activity and th at the anergy in these cells is at least in part related to the abnorm ally high activity of endogenous PTPases.