Forced expression of the Fc receptor gamma-chain renders human T cells hyperresponsive to TCR/CD3 stimulation.
High level expression of Fc epsilon RI gamma chain replaces the deficient TCR zeta-chain and contributes to altered TCR/CD3-mediated signaling abnormalities in T cells of patients with systemic lupus erythematosus. Increased responsiveness to Ag has been considered to lead to autoimmunity. To test this concept, we studied early signaling events and IL-2 production in fresh cells transfected with a eukaryotic expression vector encoding the Fc epsilon RI gamma gene. We found that the overexpressed Fc epsilon RI gamma chain colocalizes with the CD3 epsilon chain on the surface membrane of T cells and that cross-linking of the new TCR/CD3 complex leads to a dramatic increase of intracytoplasmic calcium concentration, protein tyrosine phosphorylation, and IL-2 production. We observed that overexpression of Fc epsilon RI gamma is associated with increased phosphorylation of Syk kinase, while the endogenous TCR zeta-chain is down-regulated. We propose that altered composition of the CD3 complex leads to increased T cell responsiveness to TCR/CD3 stimulation and sets the biochemical grounds for the development of autoimmunity.
Nambiar
Madhusoodana P
MP
Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Fisher
Carolyn U
CU
Kumar
Anil
A
Tsokos
Christos G
CG
Warke
Vishal G
VG
Tsokos
George C
GC
D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018274:Electroporation; D004792:Enzyme Precursors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D010766:Phosphorylation; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D017455:Receptors, IgE / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013379:Substrate Specificity / Q000235:genetics; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D004792:Enzyme Precursors; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D021122:Protein Subunits; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; D017455:Receptors, IgE; C054979:antigen T cell receptor, zeta chain; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D002118:Calcium