NFκB controls the balance between Fas and tumor necrosis factor cell death pathways during T cell receptor-induced apoptosis via the expression of its target gene A20

Abstract

Activation-induced cell death (AICD), a term originally coined for the anti-CD3-induced apoptosis of T cell hybridomas and thymocytes, is predominantly driven by death receptors and has been involved in the control of autoreactive T cells in the periphery. In the Do-11.10 T cell hybridoma model of AICD, activation of the T cell receptor (TCR) results in Fas-dependent apoptosis. Here, we show that inhibition of the transcription factor nuclear factor κB (NFκB) in Do-11.10 cells resulted in increased sensitivity to TCR-mediated apoptosis, correlating with defective induction of the anti-apoptotic NFκB target gene A20. Stable expression of the zinc finger protein A20 in NFκB-negative Do-11.10 cells rescued the phenotype. TCR activation in NFκB-deficient Do-11.10 cells resulted predominantly in tumor necrosis factor (TNF) receptor 2 (TNFR2)-dependent bystander cell death rather than classical Fas-dependent AICD. Strikingly, A20 blocked TNF-mediated apoptosis and simultaneously restored TCR-induced Fas-dependent AICD. In addition, NFκB downstream of TNFR was required for up-regulation of Fas expression by endogenous TNF secreted in response to TCR stimulation. Together, these results suggest that NFκB can play both pro- and anti-apoptotic roles during AICD. We propose that NFκB controls the balance between Fas and TNF cell death pathways during AICD via the expression of the zinc finger protein A20.