Cytotoxic activity of human dendritic cells induces RIPK1-dependent cell death

• Published in: Immunobiology (1979) Vol. 226; no. 1; p. 152032
• Main Authors: Varga, Zsófia, Rácz, Evelin, Mázló, Anett, Korodi, Mónika, Szabó, Anikó, Molnár, Tamás, Szöőr, Árpád, Veréb, Zoltán, Bácsi, Attila, Koncz, Gábor
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier GmbH 01.01.2021
• Subjects: Apoptosis; Caspase 8 - metabolism; Caspase Inhibitors - pharmacology; Cell Death; Cross-Priming; Cytotoxicity; Cytotoxicity, Immunologic; Dendritic cells; Dendritic Cells - immunology; HT29 Cells; Humans; Immune Tolerance; Immunogenic cell death; Neoplasms - immunology; Oligopeptides - pharmacology; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; RIPK1; Signal Transduction; Tumor Necrosis Factor-alpha - metabolism; Cytotoxicity; RIPK1; Dendritic cells; Immune tolerance; Immunogenic cell death
• ISSN: 0171-2985; 1878-3279
• DOI: 10.1016/j.imbio.2020.152032

•Following short-term PRR activation the supernatants of DCs induce TNF-dependent apoptosis.•Dendritic cell supernatant activates both RIPK1-dependent and -independent apoptosis.•Tolerogenic conditions reduce the cytotoxic capacity of short-term activated dendritic cells. Dendritic cells (DCs), as potent phagocytes engulf dead cells and present peptide fragments of tumor antigens or pathogens derived from infected cells to naïve CD8+ T-lymphocytes. Dendritic cells can also induce apoptosis in target cells, thus getting an opportunity to sample their microenvironment. Here, we present that the supernatants of LPS- or CL075-activated DCs induced cell death in different cell lines, but during the differentiation to mature DCs, they lost their cytotoxic potential. Dexamethasone-pre-treated tolerogenic DCs induced less intensive death indicating that the tissue microenvironment can downregulate DC-mediated killing. Exploring the signaling of DC-induced cell death, we observed that the supernatant of activated DCs induced TNF-dependent cell death, since TNF antagonist blocked the cytotoxic activity of DCs, contrary to inhibitors of Fas and TRAIL receptors. We identified that the DC-induced killing is at least partially a RIPK1-dependent process, as RIPK1 positive target cells were more susceptible to DC-induced cell death than their RIPK1 deficient counterparts. Moreover, both the elevated phosphorylation of RIPK1 and the increase in RIPK1-caspase-8 interaction in target cells suggest that RIPK1-mediated signals contribute to DC supernatant-induced cell death. We also proved that the cytotoxic activity of DC-derived supernatant induced apoptosis in the target cells and not necroptosis, as it was completely abrogated with the pan caspase inhibitor (Z-VAD), while the necroptosis inhibitor (Nec-1) had no effect. Our work revealed that the supernatant of activated DCs induces the apoptosis of target cells in a RIPK1-dependent manner. This phenomenon could be relevant for the initiation of cross-presentation and may broaden the plethora of cytotoxic mechanisms acting against tumor cells.