The phosphotyrosine phosphatase inhibitor-phenylarsine oxide restores defective phosphoinositide hydrolysis response in anergic C3H-gld/gld lymphocytes.
Mice homozygous for the gld (generalized lymphoproliferative disease) mutation develop both lymphadenopathy and autoimmune disease. CD4-CD8- (double negative, DN) T cells comprise the major population of T cells in mature C3H-gld/gld peripheral lymphoid tissues. These DN T cells are unresponsive to many forms of stimuli and have previously been shown to exhibit abnormally elevated levels of membrane phosphotyrosine phosphatase (PTPase) activity. In the present study, we demonstrate that IP3 production in response to mitogenic stimulation with Con A or anti-CD3 mAb (145-2CII) is significantly diminished in C3H-gld/gld lymphocytes when compared to that in congenic C3H(-)+/+ cells. The capacity to produce this second-messenger can be restored by pretreating C3H-gld/gld cells with the PTPase inhibitor, phenylarsine oxide (PAO). Although the inhibition of PTPase activity by treatment with PAO did restore C3H-gld/gld cell ability to produce IP3, the signal did not lead to lymphocyte proliferation, but instead to cell death. Our results suggest that the altered phosphoinositide hydrolysis observed in the mutant cells is related to their elevated membrane PTPase activity and that the anergy in these cells is at least in part related to the abnormally high activity of endogenous PTPases.
Ling
W
W
Department of Molecular and Cell Biology, University of Connecticut, Storrs 06269, USA.
Tibbetts
D J
DJ
Crain
R C
RC
Lynes
M A
MA
D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D002470:Cell Survival / Q000276:immunology; D017635:Clonal Anergy / Q000187:drug effects*; D003208:Concanavalin A / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D006868:Hydrolysis / Q000187:drug effects; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology*; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D010716:Phosphatidylinositols / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*
D001152:Arsenicals; D010716:Phosphatidylinositols; C029341:oxophenylarsine; D003208:Concanavalin A; D015544:Inositol 1,4,5-Trisphosphate; D017027:Protein Tyrosine Phosphatases