Superantigen stimulation reveals the contribution of Lck to negative regulation of T cell activation.
The conventional paradigm of T cell activation through the TCR states that Lck plays a critical activating role in this signaling process. However, the T cell response to bacterial superantigens does not require Lck. In this study we report that not only is Lck dispensable for T cell activation by superantigens, but it actively inhibits this signaling pathway. Disruption of Lck function, either by repression of Lck gene expression or by selective pharmacologic inhibitors of Lck, led to increased IL-2 production in response to superantigen stimulation. This negative regulatory effect of Lck on superantigen-induced T cell responses required the kinase activity of Lck and correlated with early TCR signaling, but was independent of immunological synapse formation and TCR internalization. Our data demonstrate that the multistage role of Lck in T cell signaling includes the activation of a negative regulatory pathway of T cell activation.
Criado
Gabriel
G
FOCIS Center for Clinical Immunology and Immunotherapeutics, Robarts Research Institute, 100 Perth Drive, London, Ontario, Canada N6A 5K8.
Madrenas
Joaquín
J
D002460:Cell Line; D002461:Cell Line, Transformed; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D004768:Enterotoxins / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011743:Pyrimidines / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000382:microbiology; D014157:Transcription Factors / Q000378:metabolism
C412373:AG 1879; D016207:Cytokines; D004268:DNA-Binding Proteins; D004768:Enterotoxins; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; D014157:Transcription Factors; C054979:antigen T cell receptor, zeta chain; C049463:enterotoxin E, Staphylococcal; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)