Lack of activation induced cell death in human T blasts despite CD95L up-regulation: protection from apoptosis by MEK signalling.
The generation of effective immunity requires that antigen-specific T cells are activated, clonally expanded and ultimately eliminated by apoptosis. The involvement of CD95-mediated apoptosis in T-cell elimination is well established, but the conditions which regulate the death pathway under normal circumstances are still emerging. Using superantigen-activated human T cells, we found that whilst T-cell receptor (TCR) signalling triggered up-regulation of CD95 ligand (CD95L), the majority of T cells were resistant to apoptosis induction, despite co-expressing high levels of CD95. Resistance was maintained following direct antibody-mediated cross-linking of CD95 and was not confined to early time periods following activation. Our data implicate TCR-derived signals in protection from apoptosis and reveal a role for the mitogen-activated protein (MAP) kinase pathway by use of a MAP kinase kinase (MEK) inhibitor. Collectively these data demonstrate that resistance to activation-induced cell death in human T cells is prolonged rather than transient, is not attributable to a lack of CD95L up-regulation and is due, at least in part, to signalling via the MEK pathway.
Walker
L S
LS
Department of Pharmacology, University of Bath, Calverton Down, Bath, BA2 7AY, UK.
McLeod
J D
JD
Boulougouris
G
G
Patel
Y I
YI
Ellwood
C N
CN
Hall
N D
ND
Sansom
D M
DM
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D001681:Biological Assay; D017252:CD3 Complex / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005419:Flavonoids; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium