1. ¹Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA
2. ²Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
3. ³Department of Medicine, Harvard Medical School, Boston, MA, USA

Correspondence: Dr KVS Prasad, Department of Microbiology and Immunology, University of Illinois at Chicago, 835 South Wolcott Avenue, Room 820, Chicago, IL 60612, USA. E-mail: kanteti@uic.edu

Received 5 May 2005; Revised 16 November 2005; Accepted 30 November 2005; Published online 20 February 2006.

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-B 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-B- 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-B activity, in TCR-mediated AICD with implications in peripheral tolerance, T-cell homeostasis and cancer.