Forced expression of the Fc Receptor gamma-chain renders human T cells hyperresponsive to TCR/CD3 stimulation

Authors:
Nambiar MP, Fisher CU, Kumar A, Tsokos CG, Warke VG and Tsokos GC
In:
J Immunol (2003) 170: 2871-2876
Research Area:
Immunotherapy / Hematology
Cells used in publication:
T cell, human peripheral blood unstim.
Species: human
Tissue Origin: blood
Experiment
In T cells of patients with systemic lupus erythematosus (SLE) high level expression of Fc epsilon RI gamma chain replaces the deficient TCR zeta-chain and contributes to altered TCR/CD3-mediated signaling abnormalities. Fc epsilon RI gamma mediates signaling by associating with the structurally homologous tyrosine phosphorylated protein kinase, Syk. In this study, the authors directly tested whether forced expression of Fc epsilon RI gamma chain in normal T cells, which do not express this molecule, would lead to increased T cell responsiveness similar to that observed in SLE T cells. Primary T cells nucleofected with an expression vector encoding Fc epsilon RI gamma showed a co-localization of Fc epsilon RI gamma with CD3epsilon. In addition, Fc epsilon RI gamma overexpression leads to an up-regulation of TCR/CD3 mediated tyrosine phosphorylation of cellular substrates and protein kinase Syk.
Abstract
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.