Bacterial Superantigens Bypass Lck-dependent T Cell Receptor Signaling by Activating a Galpha11-dependent, PLC-beta-mediated Pathway

Immunity. 2006 Jul;25(1):67-78. doi: 10.1016/j.immuni.2006.04.012.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Bacterial / immunology*
  • CD4 Antigens / immunology
  • Calcium / metabolism
  • Cells, Cultured
  • Enterotoxins / immunology
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
  • Humans
  • Interleukin-2 / biosynthesis
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Lymphocyte Activation / immunology
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
  • Phospholipase C beta
  • Phosphoserine / metabolism
  • Protein Kinase C / metabolism
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction*
  • Superantigens / immunology*
  • Type C Phospholipases / genetics
  • Type C Phospholipases / metabolism*

Substances

  • Antigens, Bacterial
  • CD4 Antigens
  • Enterotoxins
  • Interleukin-2
  • Isoenzymes
  • Receptors, Antigen, T-Cell
  • Superantigens
  • enterotoxin E, Staphylococcal
  • Phosphoserine
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Protein Kinase C
  • Extracellular Signal-Regulated MAP Kinases
  • Type C Phospholipases
  • Phospholipase C beta
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Calcium