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

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

doi:10.18632/oncotarget.19124

Meng Zhang, Fuqing Hu + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.19124

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Journal: Oncotarget	Publication Date: Jul 10, 2017
Citations: 22	License type: cc-by

Affiliation: Huazhong University of Science and Technology

Abstract

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.

Highlights

Activation-induced cell death (AICD) refers to activated T cells expressing death receptors and ligands that triggers caspase cascade, inducing suicide and fratricide by apoptosis upon persistent or repeated stimulation of their T cell receptor (TCR)
We found that transmembrane TNF-α (tmTNF-α) expression in activated T cells was upregulated, accompanied with enhanced apoptosis
This intramembrane molecule functioned as a ligand in mediation of activationinduced cell death (AICD) in T cells, similar to its soluble form, and as a receptor on activated T cells in promoting them to express FasL/ Fas, TNF-related apoptosis-inducing ligand (TRAIL)/DR4 and tmTNF-α/TNF receptor (TNFR) to increase their sensitivity to AICD (Figure 7)

Summary

Introduction

Activation-induced cell death (AICD) refers to activated T cells expressing death receptors and ligands that triggers caspase cascade, inducing suicide and fratricide by apoptosis upon persistent or repeated stimulation of their T cell receptor (TCR). AICD is induced in activated T lymphocytes via the interaction of death receptors and their cognate ligands, including Fas (CD95)/FasL, tumor necrosis factor-alpha (TNF-α)/TNF Receptor 1 (TNFR1), and TNF-related apoptosis-inducing ligand (TRAIL)/Death receptor 4 or 5 (DR4/DR5). Activation of these death receptors results in recruitment of TRADD, or/and FADD, and caspase 8, forming death-inducing signaling complexes and leading to apoptosis of activated T lymphocytes [2,3,4,5]. TmTNF-α can be hydrolyzed by TNF alpha converting enzyme (TACE) to yield sTNF-α [6, 7] These two forms of TNF-α display their activities through TNFR1 and TNFR2. TmTNF-α binds the both types of TNFR stably, it binds TNFR2 with higher affinity than sTNF-α and is a primary ligand for TNFR2 [8]

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