E2f2 Attenuates Apoptosis of Activated T Lymphocytes and Protects from Immune-Mediated Injury through Repression of Fas and FasL

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.

Role of cellular senescence genes and Immune Infiltration in sepsis and sepsis-induced ARDS based on bioinformatics analysis

“…This study suggests that E2F2 plays a critical role in regulating apoptosis and may help to design new approaches for treating immune-mediated diseases. Both in vitro and in vivo, E2f2 provides genomic stability to activated T lymphocytes and plays a speci c role in anti-apoptosis 15 . In LPS induced acute lung injury, the process of resolving lung injury, regulatory T (Treg) cells appear to be an important mediator.…”

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 exaggerates multiple organ injury, inflammation, and immune cell imbalance by activating the NF-κB pathway in sepsis

“…Possible explanations might be that (1) MALT1 could activate the NF-κB pathway, which induced apoptosis in the epithelial cells of the lung, liver, and kidney and finally caused organ injury ( Ekambaram et al, 2018 ; Sangaran et al, 2021 ). (2) MALT1 might activate T-cell receptor (TCR) signaling, which also promotes organ injury ( Govender et al, 2020 ; Mustafa et al, 2021 ). (3) MALT1 could elevate inflammation and oxidative stress, which might exaggerate organ injury as well ( Gong et al, 2022 ; He et al, 2022 ).…”

“…These findings could be explained by the following: MALT1 could activate the NF-κB pathway ( Ekambaram et al, 2018 ); meanwhile, the NF-κB pathway critically increases the levels of inflammation and oxidative stress ( Capece et al, 2022 ; Kumar et al, 2022 ). MALT1 might promote the activation of TCR signaling, which is a vital inducer of both inflammation and oxidative stress ( Mustafa et al, 2021 ). MALT1 could increase the polarization of M1 macrophages and Th17 cells, which release proinflammatory cytokines such as TNF-α, IL-1, and IL-17, thus resulting in a higher level of inflammation ( Wang et al, 2019 ; Meitei and Lal, 2022 ).…”

Possible Mechanisms of Lymphopenia in Severe Tuberculosis

“…However, the drawbacks of these treatment strategies cannot be ignored. For instance, a subset of cancers originating from the lymphatic system displays defective Fas/FasLmediated apoptosis, rendering them resistant to chemotherapy [111]. Bcl-2 is commonly overexpressed in various types of cancers, especially in lymphoma.…”