Research Papers:

Transmembrane TNF-α promotes activation-induced cell death by forward and reverse signaling

Meng Zhang, Jing Wang, Lingwei Jia, Jin Huang, Cheng He, Fuqing Hu, Lifei Yuan, Guihua Wang, Mingxia Yu and Zhuoya Li _

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Oncotarget. 2017; 8:63799-63812. https://doi.org/10.18632/oncotarget.19124

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Meng Zhang1,*, Jing Wang1,*, Lingwei Jia2, Jin Huang1, Cheng He1, Fuqing Hu2, Lifei Yuan1, Guihua Wang2, Mingxia Yu1 and Zhuoya Li1

1Department of Immunology, Basic Medical College, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China

2Molecular Medical Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China

*These authors have contributed equally to this work

Correspondence to:

Zhuoya Li, email: [email protected]

Keywords: activation-induced cell death, transmembrane TNF-α, secretory TNF-α, reverse signaling, apoptosis

Received: June 29, 2016    Accepted: June 20, 2017    Published: July 10, 2017


Secretory tumor necrosis factor-alpha (sTNF-α) is known to mediate activation- induced cell death (AICD). However, the role of tmTNF-α in AICD is still obscure. Here, we demonstrated that tmTNF-α expression significantly increased accompanied with enhanced apoptosis during AICD in Jurkat and primary human T cells. Knockdown or enhancement of tmTNF-α expression in activated T cells suppressed or promoted AICD, respectively. Treatment of activated T cells with exogenous tmTNF-α significantly augmented AICD, indicating that tmTNF-α as an effector molecule mediates AICD. As tmTNF-α can function as a receptor, an anti-TNF-α polyclonal antibody was used to trigger reverse signaling of tmTNF-α. This antibody treatment upregulated the expression of Fas ligand, TNF-related apoptosis-inducing ligand and tmTNF-α to amplify AICD, and promoted activated T cells expressing death receptor 4, TNF receptor (TNFR) 1 and TNFR2 to enhance their sensitivity to AICD. Knockdown of TNFR1 or TNFR2 expression totally blocked tmTNF-α reverse signaling increased sensitivity to sTNF-α- or tmTNF-α-mediated AICD, respectively. Our results indicate that tmTNF-α functions as a death ligand in mediation of AICD and as a receptor in sensitization of activated T cells to AICD. Targeting tmTNF-α in activated T cells may be helpful in facilitating AICD for treatment of autoimmune diseases.

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