T cell-derived tumor necrosis factor induces cytotoxicity by activating RIPK1-dependent target cell death
Ang, Rosalind L
Fairchild, Robert L
Baldwin, William M
Horwitz, Julian K
Gelles, Jesse D
Chipuk, Jerry Edward
Kelliher, Michelle A
Pavlov, Vasile I
Heeger, Peter S
Ting, Adrian T
UMass Chan AffiliationsMolecular, Cell and Cancer Biology
Document TypeJournal Article
MetadataShow full item record
AbstractTNF 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.
SourceChun N, Ang RL, Chan M, Fairchild RL, Baldwin WM 3rd, Horwitz JK, Gelles JD, Chipuk JE, Kelliher MA, Pavlov VI, Li Y, Homann D, Heeger PS, Ting AT. T cell-derived tumor necrosis factor induces cytotoxicity by activating RIPK1-dependent target cell death. JCI Insight. 2021 Dec 22;6(24):e148643. doi: 10.1172/jci.insight.148643. PMID: 34752416; PMCID: PMC8783689.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/51977
RightsCopyright: © 2021, Chun et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.; Attribution 4.0 International
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Except where otherwise noted, this item's license is described as Copyright: © 2021, Chun et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.