Reconstitution of deficient T cell receptor ζ chain restores T cell signaling and augments T cell receptor/CD3–induced interleukin‐2 production in patients with systemic lupus erythematosus

Abstract

Objective T cells from a majority of patients with systemic lupus erythematosus (SLE) display antigen receptor–mediated signaling aberrations associated with defective T cell receptor (TCR) ζ chain, a subunit of the TCR/CD3 complex. This study was undertaken to explore the possibility that forced expression of TCR ζ chain may reverse the known signaling abnormalities and defective interleukin-2 (IL-2) production in SLE T cells. Methods Freshly isolated SLE T cells were transfected with TCR ζ chain construct in a eukaryotic expression vector at high efficiency, by a recently developed nucleoporation technique. Restoration of TCR/CD3-mediated signaling was studied in the ζ chain–transfected cells. Results In SLE T cells transfected with TCR ζ chain, surface expression of TCR chain was increased and the TCR/CD3-induced increased free intracytoplasmic calcium concentration response was normalized, as was hyperphosphorylation of cellular substrates. Simultaneously, the previously noted increased expression of the Fc receptor γ chain was diminished in SLE T cells transfected with the ζ chain expression vector, and the surface membrane clusters of cell signaling molecules were redistributed to a more continuous pattern. TCR ζ chain replacement also augmented the expression of diminished TCR/CD3-mediated IL-2 production in SLE T cells, associated with increased expression of the p65 subunit of nuclear factor κB in the nuclear fractions of these T cells. Conclusion These results suggest that reconstitution of deficient TCR ζ chain can reverse the TCR/CD3-mediated signaling abnormalities as well as the defective IL-2 production in T cells of patients with SLE.