Lck is required for activation-induced T cell death after TCR ligation with partial agonists.
TCR engagement can induce either T cell proliferation and differentiation or activation-induced T cell death (AICD) through apoptosis. The intracellular signaling pathways that dictate such a disparate fate after TCR engagement have only been partially elucidated. Non-FcR-binding anti-CD3 mAbs induce a partial agonist TCR signaling pattern and cause AICD on Ag-activated, cycling T cells. In this study, we examined TCR signaling during the induction of AICD by anti-CD3 fos, a non-FcR-binding anti-CD3 mAb. This mAb activates Fyn, Lck, and extracellular signal-regulated kinase, and induces phosphorylation of Src-like adapter protein, despite the inability to cause calcium mobilization or TCR polarization. Anti-CD3 fos also fails to effectively activate zeta-associated protein of 70 kDa or NF-kappaB. Using Ag-specific T cells deficient for Fyn or Lck, we provide compelling evidence that activation of Lck is required for the induction of AICD. Our data indicate that a selective and distinct TCR signaling pattern is required for AICD by TCR partial agonist ligands.
Yu
Xue-Zhong
XZ
Human Immunogenetics Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. xyu@fhcrc.org
Levin
Steven D
SD
Madrenas
Joaquin
J
Anasetti
Claudio
C
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000941:Antigens / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D053222:Fas Ligand Protein; D007140:Immunoglobulin Fab Fragments / Q000235:genetics; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000172:deficiency / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010047:Ovalbumin / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051076:Proto-Oncogene Proteins c-fyn; D011948:Receptors, Antigen, T-Cell / Q000819:agonists* / Q000276:immunology / Q000378:metabolism*; D012995:Solubility; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology
D000911:Antibodies, Monoclonal; D000941:Antigens; D017252:CD3 Complex; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007140:Immunoglobulin Fab Fragments; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C111390:OVA 323-339; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D010047:Ovalbumin; C494960:Fyn protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium