Bacterial superantigens bypass Lck-dependent T cell receptor signaling by activating a Galpha11-dependent, PLC-beta-mediated pathway.
The paradigm to explain antigen-dependent T cell receptor (TCR) signaling is based on the activation of the CD4 or CD8 coreceptor-associated kinase Lck. It is widely assumed that this paradigm is also applicable to signaling by bacterial superantigens. However, these bacterial toxins can activate human T cells lacking Lck, suggesting the existence of an additional pathway of TCR signaling. Here we showed that this alternative pathway operates in the absence of Lck-dependent tyrosine-phosphorylation events and was initiated by the TCR-dependent activation of raft-enriched heterotrimeric Galpha11 proteins. This event, in turn, activated a phospholipase C-beta and protein kinase C-mediated cascade that turned on the mitogen-activated protein kinases ERK-1 and ERK-2, triggered Ca(2+) influx, and translocated the transcription factors NF-AT and NF-kappaB to the nucleus, ultimately inducing the production of interleukin-2 in Lck-deficient T cells. The triggering of this alternative pathway by superantigens suggests that these toxins use a G protein-coupled receptor as a coreceptor on T cells.
Bueno
Clara
C
The FOCIS Centre for Clinical Immunology and Immunotherapeutics, London, Ontario N6A 5K8, Canada.
Lemke
Caitlin D
CD
Criado
Gabriel
G
Baroja
Miren L
ML
Ferguson
Stephen S G
SS
Rahman
A K M Nur-Ur
AK
Tsoukas
Constantine D
CD
McCormick
John K
JK
Madrenas
Joaquin
J
D000942:Antigens, Bacterial / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004768:Enterotoxins / Q000276:immunology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism; D054799:Phospholipase C beta; D010768:Phosphoserine / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction; D018089:Superantigens / Q000276:immunology*; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism*
D000942:Antigens, Bacterial; D015704:CD4 Antigens; D004768:Enterotoxins; D007376:Interleukin-2; D007527:Isoenzymes; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; C049463:enterotoxin E, Staphylococcal; D010768:Phosphoserine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D010738:Type C Phospholipases; D054799:Phospholipase C beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium