title: Adjuvant-induced survival signaling in clonally expanded T cells is associated with transient increases in pAkt levels and sustained uptake of glucose.
abstract: Immunological adjuvants help increase the number of T cells responding to an immunizing antigen. Part of the increase is due to promotion of survival of clonally expanded T cells in the face of waning antigen load and subsequent growth-factor withdrawal. The phosphatidylinositide-3 kinase (PI3-kinase)/Akt pathway is activated upon T cell stimulation and plays a critical role in clonal expansion by mediating several aspects of co-stimulation in a growth-factor-dependent manner. We hypothesized that adjuvants must either cause the PI3-kinase/Akt pathway to operate in the absence of growth-factor or to render T cells independent of continuous PI3-kinase signaling for their survival. To determine which is true, mice were treated with model antigen in the presence or absence of the natural adjuvant lipopolysaccharide (LPS). T cells from treated mice were assayed for their dependence on PI3-kinase signaling by measuring (i) levels of phosphorylated Akt, (ii) survival after culture in the presence of the PI3-kinase inhibitor LY294002, and (iii) the amount of glucose uptake upon ex vivo culture. The results show that although LPS treatment increased the induced PI3-kinase activity, the presence of PI3-kinase inhibitor did not affect glucose uptake or survival of T cells, an attribute the cells acquired within 4 h of LPS injection. Therefore, adjuvant-dependent survival effects do not require continuous PI3-kinase activity to occur, a finding that may explain how activated T cells survive antigen-withdrawal long enough to traffic from priming lymph nodes to sites of infection.
authors.affiliation: Institute for Cellular Therapeutics, University of Louisville School of Medicine, KY 40202, USA.
authors.forename: Sadhak
authors.initials: S
authors.lastname: Sengupta
authors.forename: Paula M
authors.initials: PM
authors.lastname: Chilton
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Mitchell
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D005260:Female; D005947:Glucose / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D013997:Time Factors
chemical_list: D000276:Adjuvants, Immunologic; D016895:Culture Media, Serum-Free; D005947:Glucose; D008070:Lipopolysaccharides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors