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Abstract
Targeted disruption of E2f2 in mice causes T-cell hyperactivation and a disproportionate cell cycle entry upon stimulation. However, E2f2−/− mice do not develop a lymphoproliferative condition. We report that E2f2 plays a Fas-dependent anti-apoptotic function in vitro and in vivo. TCR-stimulated murine E2f2−/− T cells overexpress the proapoptotic genes Fas and FasL and exhibit enhanced apoptosis, which is prevented by treatment with neutralizing anti-FasL antibodies. p53 pathway is activated in TCR-stimulated E2f2−/− lymphocytes, but targeted disruption of p53 in E2f2−/− mice does not abrogate Fas/FasL expression or apoptosis, implying a p53-independent apoptotic mechanism. We show that E2f2 is recruited to Fas and FasL gene promoters to repress their expression. in vivo, E2f2−/− mice are prone to develop immune-mediated liver injury owing to an aberrant lymphoid Fas/FasL activation. Taken together, our results suggest that E2f2-dependent inhibition of Fas/FasL pathway may play a direct role in limiting the development of immune-mediated pathologies.
Highlights
IntroductionUpon recognition of a foreign antigen, naïve T cells carrying antigen-specific T-cell receptor (TCR) grow in size while firing a robust proliferation and differentiation program [2]
T-cell homeostasis is triggered by signals emanated from the T-cell receptor (TCR) [1].Upon recognition of a foreign antigen, naïve T cells carrying antigen-specific TCRs grow in size while firing a robust proliferation and differentiation program [2]
We analyzed the proliferation and viability of purified T lymphocytes derived from the lymph nodes of wild-type (WT) and E2f2−/− mice at several time points after stimulation with a TCR-activating anti-CD3 antibody
Summary
Upon recognition of a foreign antigen, naïve T cells carrying antigen-specific TCRs grow in size while firing a robust proliferation and differentiation program [2]. This is closely followed by the induction of apoptosis, in order to prevent a hyperactive T-cell population from overreaction once the pathogen has been cleared [3]. E2f2−/− mice develop a late-onset disorder with autoimmune features [4]. Some of these effects have been attributed to the transcriptional overexpression of cell cycle genes in knockout animals [6], but the underlying mechanisms remain to be fully elucidated [4]
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