A Splice Variant of the TCR ζ mRNA Lacking Exon 7 Leads to the Down-Regulation of TCR ζ, the TCR/CD3 Complex, and IL-2 Production in Systemic Lupus Erythematosus T Cells

The reduction or absence of TCR zeta-chain (zeta) expression in patients with systemic lupus erythematosus (SLE) is thought to be a factor in the pathogenesis of SLE. We previously reported a splice variant of zeta mRNA that lacks the 36-bp exon 7 (zeta mRNA/exon 7(-)) and is accompanied by the down-regulation of zeta protein in T cells from SLE patients. In this study, we show that EX7- mutants (MA5.8 cells deficient in zeta protein that have been transfected with zeta mRNA/exon 7(-)) exhibit a reduction in the expression of TCR/CD3 complex and zeta protein on their cell surface as well as a reduction in the production of IL-2 after stimulation with anti-CD3 Ab, compared with that in wild-type (WT) mutants (MA5.8 cells transfected with the WT zeta mRNA). Furthermore, real-time PCR analyses demonstrated that zeta mRNA/exon 7(-) in EX7- mutants was easily degraded compared with zeta mRNA by the WT mutants. Pulse-chase experiment showed zeta protein produced by this EX7- mutants was more rapidly decreased compared with the WT mutants. Thus, the lower stability of zeta mRNA/exon 7(-) might also be responsible for the reduced expression of the TCR/CD3 complex, including zeta protein, in SLE T cells.