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T cell–derived tumor necrosis factor induces cytotoxicity by activating RIPK1-dependent target cell death
Nicholas Chun, … , Peter S. Heeger, Adrian T. Ting
Nicholas Chun, … , Peter S. Heeger, Adrian T. Ting
Published November 9, 2021
Citation Information: JCI Insight. 2021;6(24):e148643. https://doi.org/10.1172/jci.insight.148643.
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Research Article Cell biology Immunology

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

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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.

Authors

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

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Figure 1

TNF-modulated, RIPK1-dependent cell death mediates graft rejection and intragraft cell death.

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TNF-modulated, RIPK1-dependent cell death mediates graft rejection and i...
(A–D) Kaplan-Meier survival curves for WT or genetically distinct B6 heart grafts subjected to 8 hours (8h) of CIS and transplanted into CTLA4Ig-treated BALB/c recipients. (A) WT B6 hearts into recipients treated with anti-TNF mAb (n = 5) or isotype IgG (n = 3) control on the day of surgery. (B) WT B6 hearts into recipients treated with necrostatin-1 (n = 8) or vehicle control (n = 4) on the day of surgery. (C) Ripk1D138N (n = 6), Mlkl–/– (n = 6), Ripk3–/– (n = 5), or WT (n = 8) B6 allografts. *P < 0.05 versus WT control. (D) WT (same data as shown in C) or Sharpincpdm B6 allografts transplanted into WT BALB/c recipients ± anti-TNF blocking mAb (αTNF, day 0, then every 5 days for 2 weeks, n = 5) or equivalent dosing of IgG isotype control (isotype n = 4, P < 0.05 versus IgG control). (E) Representative TUNEL staining (arrowheads) and quantification of day-7 posttransplant WT and RIPK1D138N B6 hearts in WT BALB/c recipients (n = 4–5). Each dot represents a biological replicate. P < 0.05 versus WT control, t test. (F) Representative TUNEL staining and quantification of WT B6 allografts transplanted as described above into BALB/c hosts treated with anti-TNF mAb or isotype control (n = 5–6, t test). (G) Representative TUNEL staining and quantification of Sharpincpdm B6 allografts transplanted as described above into BALB/c hosts treated with anti-TNF mAb or isotype control (n = 4–5). *P < 0.05. Scale bars: 100 μm. Survival statistics for A–D calculated by Mantel Cox log rank test. Quantitative statistics for E–G calculated by t test.

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