Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations
Stimulator of Interferon Genes (STING) is a cytosolic sensor of cyclic dinucleotides (CDNs). The activation of dendritic cells (DC) via the STING pathway, and their subsequent production of type I interferon (IFN) is considered central to eradicating tumours in mouse models. However, this contributi...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.794776/full |
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| author | Ee Shan Pang Ghazal Daraj Katherine R. Balka Dominic De Nardo Christophe Macri Hubertus Hochrein Kelly-Anne Masterman Peck S. Tan Angus Shoppee Zoe Magill Nazneen Jahan Mariam Bafit Yifan Zhan Yifan Zhan Benjamin T. Kile Benjamin T. Kile Kate E. Lawlor Kate E. Lawlor Kristen J. Radford Mark D. Wright Meredith O’Keeffe |
| author_facet | Ee Shan Pang Ghazal Daraj Katherine R. Balka Dominic De Nardo Christophe Macri Hubertus Hochrein Kelly-Anne Masterman Peck S. Tan Angus Shoppee Zoe Magill Nazneen Jahan Mariam Bafit Yifan Zhan Yifan Zhan Benjamin T. Kile Benjamin T. Kile Kate E. Lawlor Kate E. Lawlor Kristen J. Radford Mark D. Wright Meredith O’Keeffe |
| author_sort | Ee Shan Pang |
| collection | DOAJ |
| description | Stimulator of Interferon Genes (STING) is a cytosolic sensor of cyclic dinucleotides (CDNs). The activation of dendritic cells (DC) via the STING pathway, and their subsequent production of type I interferon (IFN) is considered central to eradicating tumours in mouse models. However, this contribution of STING in preclinical murine studies has not translated into positive outcomes of STING agonists in phase I & II clinical trials. We therefore questioned whether a difference in human DC responses could be critical to the lack of STING agonist efficacy in human settings. This study sought to directly compare mouse and human plasmacytoid DCs and conventional DC subset responses upon STING activation. We found all mouse and human DC subsets were potently activated by STING stimulation. As expected, Type I IFNs were produced by both mouse and human plasmacytoid DCs. However, mouse and human plasmacytoid and conventional DCs all produced type III IFNs (i.e., IFN-λs) in response to STING activation. Of particular interest, all human DCs produced large amounts of IFN-λ1, not expressed in the mouse genome. Furthermore, we also found differential cell death responses upon STING activation, observing rapid ablation of mouse, but not human, plasmacytoid DCs. STING-induced cell death in murine plasmacytoid DCs occurred in a cell-intrinsic manner and involved intrinsic apoptosis. These data highlight discordance between STING IFN and cell death responses in mouse and human DCs and caution against extrapolating STING-mediated events in mouse models to equivalent human outcomes. |
| first_indexed | 2024-12-20T17:02:12Z |
| format | Article |
| id | doaj.art-70cc408876864abf9485d6da1eda5714 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T17:02:12Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-70cc408876864abf9485d6da1eda57142022-12-21T19:32:28ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-02-011310.3389/fimmu.2022.794776794776Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell PopulationsEe Shan Pang0Ghazal Daraj1Katherine R. Balka2Dominic De Nardo3Christophe Macri4Hubertus Hochrein5Kelly-Anne Masterman6Peck S. Tan7Angus Shoppee8Zoe Magill9Nazneen Jahan10Mariam Bafit11Yifan Zhan12Yifan Zhan13Benjamin T. Kile14Benjamin T. Kile15Kate E. Lawlor16Kate E. Lawlor17Kristen J. Radford18Mark D. Wright19Meredith O’Keeffe20Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaTranslational Research Institute, Mater Research-University of Queensland, Woolloongabba, QLD, AustraliaDepartment of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaDepartment of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaDepartment of Research, Bavarian Nordic GmbH, Martinsried, GermanyTranslational Research Institute, Mater Research-University of Queensland, Woolloongabba, QLD, AustraliaDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaImmunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, AustraliaDepartment of Medical Biology, University of Melbourne, Parkville, VIC, AustraliaDepartment of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaFaculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, AustraliaCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, AustraliaDepartment of Molecular and Translational Science, Monash University, Clayton, VIC, AustraliaTranslational Research Institute, Mater Research-University of Queensland, Woolloongabba, QLD, Australia0Department of Immunology and Pathology, Monash University, Melbourne, VIC, AustraliaDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaStimulator of Interferon Genes (STING) is a cytosolic sensor of cyclic dinucleotides (CDNs). The activation of dendritic cells (DC) via the STING pathway, and their subsequent production of type I interferon (IFN) is considered central to eradicating tumours in mouse models. However, this contribution of STING in preclinical murine studies has not translated into positive outcomes of STING agonists in phase I & II clinical trials. We therefore questioned whether a difference in human DC responses could be critical to the lack of STING agonist efficacy in human settings. This study sought to directly compare mouse and human plasmacytoid DCs and conventional DC subset responses upon STING activation. We found all mouse and human DC subsets were potently activated by STING stimulation. As expected, Type I IFNs were produced by both mouse and human plasmacytoid DCs. However, mouse and human plasmacytoid and conventional DCs all produced type III IFNs (i.e., IFN-λs) in response to STING activation. Of particular interest, all human DCs produced large amounts of IFN-λ1, not expressed in the mouse genome. Furthermore, we also found differential cell death responses upon STING activation, observing rapid ablation of mouse, but not human, plasmacytoid DCs. STING-induced cell death in murine plasmacytoid DCs occurred in a cell-intrinsic manner and involved intrinsic apoptosis. These data highlight discordance between STING IFN and cell death responses in mouse and human DCs and caution against extrapolating STING-mediated events in mouse models to equivalent human outcomes.https://www.frontiersin.org/articles/10.3389/fimmu.2022.794776/fullSTING activationdendritic cell (DC)interferon-lambdahuman dendritic cellstype III interferonscell death |
| spellingShingle | Ee Shan Pang Ghazal Daraj Katherine R. Balka Dominic De Nardo Christophe Macri Hubertus Hochrein Kelly-Anne Masterman Peck S. Tan Angus Shoppee Zoe Magill Nazneen Jahan Mariam Bafit Yifan Zhan Yifan Zhan Benjamin T. Kile Benjamin T. Kile Kate E. Lawlor Kate E. Lawlor Kristen J. Radford Mark D. Wright Meredith O’Keeffe Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations Frontiers in Immunology STING activation dendritic cell (DC) interferon-lambda human dendritic cells type III interferons cell death |
| title | Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations |
| title_full | Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations |
| title_fullStr | Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations |
| title_full_unstemmed | Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations |
| title_short | Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations |
| title_sort | discordance in sting induced activation and cell death between mouse and human dendritic cell populations |
| topic | STING activation dendritic cell (DC) interferon-lambda human dendritic cells type III interferons cell death |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.794776/full |
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