Unrestrained glycogen synthase kinase-3 beta activity leads to activated T cell death and can be inhibited by natural adjuvant.
Activated T cell death (ATCD) after peak clonal expansion is required for effective homeostasis of the immune system. Using a mouse model of T cell clonal expansion and contraction, we found that regulation of the proapoptotic kinase glycogen synthase kinase (GSK)-3beta plays a decisive role in determining the extent to which T cells are eliminated after activation. Involvement of GSK-3beta in ATCD was tested by measuring T cell survival after GSK-3beta inhibition, either ex vivo with chemical and pharmacological inhibitors or in vivo by retroviral expression of a dominant-negative form of GSK-3. We also measured amounts of inactivating phosphorylation of GSK-3beta (Ser9) in T cells primed in the presence or absence of LPS. Our results show that GSK-3beta activity is required for ATCD and that its inhibition promoted T cell survival. Adjuvant treatment in vivo maintained GSK-3beta (Ser9) phosphorylation in activated T cells, whereas with adjuvant-free stimulation it peaked and then decayed as the cells became susceptible to ATCD. We conclude that the duration of GSK-3beta inactivation determines activated T cell survival and that natural adjuvant stimulation decreases the severity of clonal contraction in part by keeping a critical proapoptotic regulatory factor, GSK-3beta, inactivated.
Sengupta
Sadhak
S
Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville School of Medicine, KY 40202, USA.
Jayaraman
Padmini
P
Chilton
Paula M
PM
Casella
Carolyn R
CR
Mitchell
Thomas C
TC
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*
D000276:Adjuvants, Immunologic; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3