T cell long-term hyporesponsiveness follows antigen receptor engagement and results from defective signal transduction.
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.
Dubois
P M
PM
Laboratoire de Physiologie Animale, Universite Libre de Bruxelles, Belgium.
Andris
F
F
Shapiro
R A
RA
Gilliland
L K
LK
Kaufman
M
M
Urbain
J
J
Ledbetter
J A
JA
Leo
O
O
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
D007295:Inositol Phosphates; D011948:Receptors, Antigen, T-Cell; D011976:Receptors, Muscarinic; D011505:Protein-Tyrosine Kinases; D010738:Type C Phospholipases