title: Antigenic experience dictates functional role of glycogen synthase kinase-3 in human CD4+ T cell responses.
abstract: Signals induced by the TCR and CD28 costimulatory pathway have been shown to lead to the inactivation of the constitutively active enzyme, glycogen synthase kinase-3 (GSK3), which has been implicated in the regulation of IL-2 and T cell proliferation. However, it is unknown whether GSK3 plays a similar role in naive and memory CD4(+) T cell responses. Here we demonstrate a divergence in the dependency on the inactivation of GSK3 in the proliferative responses of human naive and memory CD4(+) T cells. We find that although CD28 costimulation increases the frequency of phospho-GSK3 inactivation in TCR-stimulated naive and memory CD4(+) T cells, memory cells are less reliant on GSK3 inactivation for their proliferative responses. Rather we find that GSK3beta plays a previously unrecognized role in the selective regulation of the IL-10 recall response by human memory CD4(+) T cells. Furthermore, GSK3beta-inactivated memory CD4(+) T cells acquired the capacity to suppress the bystander proliferation of CD4(+) T cells in an IL-10-dependent, cell contact-independent manner. Our findings reveal a dichotomy present in the function of GSK3 in distinct human CD4(+) T cell populations.
authors.affiliation: Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Garcia
authors.forename: Manjunatha R
authors.initials: MR
authors.lastname: Benakanakere
authors.forename: Pascale
authors.initials: P
authors.lastname: Alard
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Kosiewicz
authors.forename: Denis F
authors.initials: DF
authors.lastname: Kinane
authors.forename: Michael
authors.initials: M
authors.lastname: Martin
mesh_terms: D000328:Adult; D024201:Bystander Effect / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism
chemical_list: D016753:Interleukin-10; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3