The balance of protein kinase C and calcium signaling directs T cell subset development.
Development of naive T cells into type 1 (Th1, Tc1) or type 2 (Th2, Tc2) effector cells is thought to be under the control of cytokines. In this study, we show that when both IL-12 and IL-4 are present, murine and human T cell differentiation is regulated by the balance of protein kinase C (PKC) and calcium signaling within T cells. Although both biochemical signals were required for T cell activation via the TCR, altering the balance between them redirected type 1 cells to type 2 and vice versa. Stimulation of calcium signaling or inhibition of PKC favored type 1 differentiation, whereas stimulation of PKC or inhibition of calcineurin resulted in type 2 effectors. Altered peptide ligands induced distinct balances of PKC/calcium signaling and altered Tc1/Tc2 development in TCR-transgenic CD8 T cells. The data suggest novel strategies for manipulation of the immune response in vivo.
Noble
A
A
Department of Immunology, Guy's, King's, and St. Thomas' School of Medicine, Rayne Institute, London, United Kingdom. alistair.noble@kcl.ac.uk
Truman
J P
JP
Vyas
B
B
Vukmanovic-Stejic
M
M
Hirst
W J
WJ
Kemeny
D M
DM
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D019703:Calcineurin / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002999:Clone Cells; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018418:Th2 Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism
D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D015759:Ionomycin; D011493:Protein Kinase C; D019703:Calcineurin; D013755:Tetradecanoylphorbol Acetate