title: T cell long-term hyporesponsiveness follows antigen receptor engagement and results from defective signal transduction.
abstract: T cell receptor (TCR)-mediated stimulation of T hybridomas leads to cell activation and lymphokine production that is followed by a long-term hyporesponsiveness. To investigate the biochemical events involved in the induction and maintenance of this antigen receptor hyporesponsiveness or anergy, we have expressed a G protein/PLC beta 1-coupled muscarinic subtype 1 acetylcholine receptor in a murine T cell hybrid. Transfected cells were capable of responding to both muscarinic agonists and TCR ligands by inducing interleukin-2 secretion that was sensitive to cyclosporin A and dexamethasone. Both receptors induced tyrosine kinase (TK) activity, but muscarinic stimulation did not affect tyrosine phosphorylation of PLC gamma 1, nor did the TK inhibitor, herbimycin, block muscarinic receptor-mediated calcium mobilization. These data indicate that in T cells, the muscarinic receptor mediates T cell effector functions by regulating a TK-independent proximal pathway which later converges with the TCR pathway. Using these cells, we have explored the long-term consequences of T cell stimulation via antigen or muscarinic receptors. Our results show that hyporesponsiveness specifically follows TCR engagement and appears to result from a defect in the early signal transduction initiated by TCR cross-linking. A study of TCR-mediated signaling supports this model by showing that tyrosine phosphorylation and calcium mobilization are deficient in hyporesponsive T cells.
authors.affiliation: Laboratoire de Physiologie Animale, Universite Libre de Bruxelles, Belgium.
authors.forename: P M
authors.initials: PM
authors.lastname: Dubois
authors.forename: F
authors.initials: F
authors.lastname: Andris
authors.forename: R A
authors.initials: RA
authors.lastname: Shapiro
authors.forename: L K
authors.initials: LK
authors.lastname: Gilliland
authors.forename: M
authors.initials: M
authors.lastname: Kaufman
authors.forename: J
authors.initials: J
authors.lastname: Urbain
authors.forename: J A
authors.initials: JA
authors.lastname: Ledbetter
authors.forename: O
authors.initials: O
authors.lastname: Leo
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D004306:Dose-Response Relationship, Immunologic; D007108:Immune Tolerance; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011976:Receptors, Muscarinic / Q000276:immunology; D015290:Second Messenger Systems; D015398:Signal Transduction; D013997:Time Factors; D010738:Type C Phospholipases / Q000502:physiology
chemical_list: D007295:Inositol Phosphates; D011948:Receptors, Antigen, T-Cell; D011976:Receptors, Muscarinic; D011505:Protein-Tyrosine Kinases; D010738:Type C Phospholipases