Pretreatment of cloned helper T lymphocytes with IL-2 induces unresponsiveness to antigen and concanavalin A, associated with decreased inositol phosphate and diacylglycerol production.
IL-2 pretreatment of cloned Th lymphocytes has been demonstrated to render these cells unresponsive to subsequent stimulation through the TCR. These cells remain unresponsive for up to 7 days after removal from IL-2. Cells rendered unresponsive to Ag by pretreatment with IL-2 also demonstrated reduced increases in intracellular calcium ([Ca2+]i) after stimulation, hence this unresponsiveness is believed to result from absence of sufficient [Ca2+]i for activation of lymphokine genes. We have confirmed these observations, and demonstrate that only that portion of the [Ca2+]i increase derived from extracellular sources is inhibited in IL-2 pretreated cells. Further, inositol degradation and diacylglycerol production after stimulation are observed to be markedly reduced in cells rendered unresponsive by IL-2 pretreatment, suggesting that signal transduction leading to cleavage of phosphatidylinositol 4,5-bisphosphate after Ag receptor engagement is incomplete in these cells. However, treatment of IL-2 pretreated cells with AlF4- results in both production of inositol phosphates as well as increased intracellular calcium, suggesting that phospholipase C remains active in these cells. It appears that chronic IL-2 exposure regulates Th activation by inhibiting the signal transduction which follows engagement of the TCR.
Schell
S R
SR
Department of Pathology, University of Chicago, Pritzker School of Medicine, IL 60637.
Fitch
F W
FW
D000535:Aluminum / Q000494:pharmacology; D017607:Aluminum Compounds; D000818:Animals; D000941:Antigens / Q000276:immunology; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002999:Clone Cells / Q000276:immunology; D003208:Concanavalin A / Q000494:pharmacology; D004075:Diglycerides / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005110:Extracellular Space / Q000378:metabolism; D005459:Fluorides / Q000494:pharmacology; D005989:Glycerides / Q000096:biosynthesis*; D007108:Immune Tolerance; D007295:Inositol Phosphates / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D013403:Sugar Phosphates / Q000096:biosynthesis*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D017607:Aluminum Compounds; D000941:Antigens; D004075:Diglycerides; D005989:Glycerides; D007295:Inositol Phosphates; D007376:Interleukin-2; D013403:Sugar Phosphates; D003208:Concanavalin A; D000535:Aluminum; D005459:Fluorides; D002118:Calcium; C032311:aluminum fluoride