IL-2 secretion and T cell clonal anergy are induced by distinct biochemical pathways.
In Th1 clones, TCR occupancy together with a costimulatory signal from APC results in IL-2 production. TCR occupancy alone results in unresponsiveness (anergy) to antigenic stimulation, a phenomenon that may be important for self-tolerance in vivo. Inasmuch as inositol phosphate production occurs during the induction of anergy other biochemical signals must be necessary for IL-2 production. Here we assess the role of tyrosine-specific protein kinases using the specific inhibitor, genistein. IL-2 secretion and responsiveness were very dependent on tyrosine-specific protein kinase activation and could be completely blocked under conditions where inositol phosphate generation occurred normally. Although anergy induction could also be blocked by inhibition of tyrosine-specific protein kinase activation this probably occurred indirectly via inhibition of inositol phospholipid hydrolysis. The differential susceptibility of IL-2 secretion and anergy induction to inhibition by genistein indicates that positive and negative outcomes of TCR occupancy may be mediated by distinct biochemical pathways.
Norton
S D
SD
Department of Microbiology, University of Minnesota Medical School, Minneapolis 55455.
Hovinen
D E
DE
Jenkins
M K
MK
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000941:Antigens / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002999:Clone Cells; D019833:Genistein; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007295:Inositol Phosphates / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000378:metabolism*; D007529:Isoflavones / Q000494:pharmacology; D051379:Mice; D010716:Phosphatidylinositols / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
D000941:Antigens; D007295:Inositol Phosphates; D007376:Interleukin-2; D007529:Isoflavones; D010716:Phosphatidylinositols; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D002118:Calcium