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-FLIPshort 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.
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Acknowledgements
We thank Drs B. Prabhakar and C. Vasu (UIC) for helpful comments and Drs T. Hope (North Western University) and B. Cullen (Duke University) for providing the lentiviral siRNA vector. The anti-CD3 antibodies (OKT3 and 2C11) and anti-FLIP (NF-6) antibody were kind gifts from Drs Gordon Freeman (Harvard University) and Marcus Peter (University of Chicago), respectively.
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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)
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Gudi, R., Barkinge, J., Hawkins, S. et al. Siva-1 negatively regulates NF-κB activity: effect on T-cell receptor-mediated activation-induced cell death (AICD). Oncogene 25, 3458–3462 (2006). https://doi.org/10.1038/sj.onc.1209381
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DOI: https://doi.org/10.1038/sj.onc.1209381
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