A splice variant of the TCR zeta mRNA lacking exon 7 leads to the down-regulation of TCR zeta, the TCR/CD3 complex, and IL-2 production in systemic lupus erythematosus T cells

• Published in: The Journal of immunology (1950) Vol. 174; no. 6; pp. 3518 - 3525
• Main Authors: Tsuzaka, Kensei, Setoyama, Yumiko, Yoshimoto, Keiko, Shiraishi, Kiyono, Suzuki, Katsuya, Abe, Tohru, Takeuchi, Tsutomu
• Format: Journal Article
• Language: English
• Published: United States 15-03-2005
• Subjects: Alternative Splicing; Animals; Cell Line; Down-Regulation; Exons; Humans; Hybridomas; Interleukin-2 - biosynthesis; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Receptor-CD3 Complex, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; RNA Stability; RNA, Messenger - genetics; RNA, Messenger - metabolism; T-Lymphocytes - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.174.6.3518

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.