Abstract
Ligation of TCRs on stimulated T cells leads to activation-induced cell death (AICD) resulting in the downregulation of immune responses, a process essential for T-cell homeostasis. In this study, using transformed T-cell lines such as Jurkat and Do11.10 as cellular models of TCR-mediated AICD, we have demonstrated that the proapoptotic protein Siva-1 is required for TCR-induced apoptosis. Knockdown of Siva-1 rendered T cells specifically resistant to anti-CD3 but not Fas-induced apoptosis. Further, we observed that in Siva-1 knockout Jurkat cells, TCR-mediated activation of the canonical and non-canonical limbs of the NF-κB pathway are significantly enhanced as reflected by elevated nuclear levels of p65 and RelB, respectively. In addition, loss of endogenous Siva-1 also resulted in the enhanced expression of NF-κB- responsive anti-apoptotic genes such as Bcl-xL and c-FLIP. Interestingly, the c-FLIP(short) was detected only in TCR-ligated Siva-1 knockdown Jurkat cells. These results demonstrate a significant role for endogenous Siva-1, through its inhibitory effect on NF-κB activity, in TCR-mediated AICD with implications in peripheral tolerance, T-cell homeostasis and cancer.
Original language | English (US) |
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Pages (from-to) | 3458-3462 |
Number of pages | 5 |
Journal | Oncogene |
Volume | 25 |
Issue number | 24 |
DOIs | |
State | Published - Jun 8 2006 |
Externally published | Yes |
Keywords
- AICD
- Apoptosis
- Bcl-xL
- NF-κB
- TCR
- c-FLIP
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research