T cell-derived tumor necrosis factor induces cytotoxicity by activating RIPK1-dependent target cell death.

Nicholas Chun,Robert L Fairchild,Yansui Li,Peter S Heeger,Jesse D Gelles,Julian K Horwitz,Michelle A Kelliher,William M Baldwin,Jerry Edward Chipuk,Dirk Homann,Vasile I Pavlov,Rosalind L Ang,Adrian T Ting,Mark Chan

doi:10.1172/jci.insight.148643

Abstract

TNF ligation of TNF receptor 1 (TNFR1) promotes either inflammation and cell survival by (a) inhibiting RIPK1’s death-signaling function and activating NF-κB or (b) causing RIPK1 to associate with the death-inducing signaling complex to initiate apoptosis or necroptosis. The cellular source of TNF that results in RIPK1-dependent cell death remains unclear. To address this, we employed in vitro systems and murine models of T cell–dependent transplant or tumor rejection in which target cell susceptibility to RIPK1-dependent cell death could be genetically altered. We show that TNF released by T cells is necessary and sufficient to activate RIPK1-dependent cell death in target cells and thereby mediate target cell cytolysis independently of T cell frequency. Activation of the RIPK1-dependent cell death program in target cells by T cell–derived TNF accelerates murine cardiac allograft rejection and synergizes with anti-PD1 administration to destroy checkpoint blockade–resistant murine melanoma. Together, the findings uncover a distinct immunological role for TNF released by cytotoxic effector T cells following cognate interactions with their antigenic targets. Manipulating T cell TNF and/or target cell susceptibility to RIPK1-dependent cell death can be exploited to either mitigate or augment T cell–dependent destruction of allografts and malignancies to improve outcomes.

Highlights

TNF is a pleiotropic cytokine produced by multiple cell types, including monocytes, macrophages, T cells, and endothelial cells [1,2,3]
To initially extend previously published work by others associating donor RIPK3 deficiency with delayed allograft rejection [43, 44], we employed a distinct model of murine heterotopic heart transplantation in which the donor organ is subjected to prolonged cold ischemic storage (CIS)
We examined whether RIPK1-dependent cell death participates in the rejection of grafts exposed to prolonged CIS using necrostatin-1, a small molecule that inhibits the kinase activity of RIPK1 previously shown by others to prevent programmed cell death [51]

Summary

Introduction

TNF is a pleiotropic cytokine produced by multiple cell types, including monocytes, macrophages, T cells, and endothelial cells [1,2,3]. These modifications serve to inhibit RIPK1 from interacting with the death signaling complex (known as complex II) containing FADD, CASPASE 8, and RIPK3 [15,16,17,18]. Both forms of cell death are dependent on the kinase activity of RIPK1

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Results

Conclusion