Non-apoptotic TRAIL function modulates NK cell activity during viral infection

Ludmila Cardoso Alves; Michael D. Berger; Thodoris Koutsandreas; Nick Kirschke; Christoph Lauer; Roman Spörri; Aristotelis Chatziioannou; Nadia Corazza; Philippe Krebs

doi:10.15252/embr.201948789

Non-apoptotic TRAIL function modulates NK cell activity during viral infection

Ludmila Cardoso Alves, Michael D. Berger, Thodoris Koutsandreas, Nick Kirschke, Christoph Lauer, Roman Spörri, Aristotelis Chatziioannou, Nadia Corazza, Philippe Krebs^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

The role of death receptor signaling for pathogen control and infection-associated pathogenesis is multifaceted and controversial. Here, we show that during viral infection, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) modulates NK cell activity independently of its pro-apoptotic function. In mice infected with lymphocytic choriomeningitis virus (LCMV), Trail deficiency led to improved specific CD8⁺ T-cell responses, resulting in faster pathogen clearance and reduced liver pathology. Depletion experiments indicated that this effect was mediated by NK cells. Mechanistically, TRAIL expressed by immune cells positively and dose-dependently modulates IL-15 signaling-induced granzyme B production in NK cells, leading to enhanced NK cell-mediated T cell killing. TRAIL also regulates the signaling downstream of IL-15 receptor in human NK cells. In addition, TRAIL restricts NK1.1-triggered IFNγ production by NK cells. Our study reveals a hitherto unappreciated immunoregulatory role of TRAIL signaling on NK cells for the granzyme B-dependent elimination of antiviral T cells.

Original language	American English
Article number	e48789
Journal	EMBO Reports
Volume	21
Issue number	1
DOIs	https://doi.org/10.15252/embr.201948789
State	Published - 7 Jan 2020
Externally published	Yes

Bibliographical note

Funding Information:
We thank Regula Stuber for her excellent technical support. We are grateful to Annette Oxenius (ETH Zurich, Switzerland) and Eva Szegezdi (NUI, Galway, Ireland) for providing us with reagents and to Vladimir Benes (GeneCore, Heidelberg, Germany) for advice on RNA isolation methods. We also like to extend our gratitude toward Haifeng C. Xu, Werner Held, Stefan Freigang, Daniel L. Popkin, Antoine Marçais, Christian M. Schürch, Mario Noti, and Lukas F. Mager for advice or critical comments. This work was supported by grants from the Swiss National Science Foundation (310030_138188 and 314730_163086), the “Vontobel Stiftung”, the “Olga Mayenfisch Stiftung”, the “Kurt und Senta Herrmann?Stiftung”, a generous donor advised by CARIGEST SA, the Bern University Research Foundation (all to P.K.). This project has also received funding from the European Union Seventh Framework Program (FP7) under grant agreement No PCIG12-GA-2012-334081 (X-talk) (to P.K.) and the European Union's Horizon 2020 research and innovation program under the Marie Sk?odowska-Curie grant agreement No 777995 (DISCOVER) (to P.K. and A.C.).

Funding Information:
We thank Regula Stuber for her excellent technical support. We are grateful to Annette Oxenius (ETH Zurich, Switzerland) and Eva Szegezdi (NUI, Galway, Ireland) for providing us with reagents and to Vladimir Benes (GeneCore, Heidelberg, Germany) for advice on RNA isolation methods. We also like to extend our gratitude toward Haifeng C. Xu, Werner Held, Stefan Freigang, Daniel L. Popkin, Antoine Marçais, Christian M. Schürch, Mario Noti, and Lukas F. Mager for advice or critical comments. This work was supported by grants from the Swiss National Science Foundation (310030_138188 and 314730_163086), the “Vontobel Stiftung”, the “Olga Mayenfisch Stiftung”, the “Kurt und Senta Herrmann?Stiftung”, a generous donor advised by CARIGEST SA, the Bern University Research Foundation (all to P.K.). This project has also received funding from the European Union Seventh Framework Program (FP7) under grant agreement No PCIG12‐GA‐2012‐334081 (X‐talk) (to P.K.) and the European Union's Horizon 2020 research and innovation program under the Marie Sk?odowska‐Curie grant agreement No 777995 (DISCOVER) (to P.K. and A.C.).

Publisher Copyright:
© 2019 The Authors. Published under the terms of the CC BY 4.0 license

Keywords

CD8 T cells
IL-15 signaling
NK cells
TNF-related apoptosis-inducing ligand
lymphocytic choriomeningitis virus

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10.15252/embr.201948789

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title = "Non-apoptotic TRAIL function modulates NK cell activity during viral infection",

abstract = "The role of death receptor signaling for pathogen control and infection-associated pathogenesis is multifaceted and controversial. Here, we show that during viral infection, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) modulates NK cell activity independently of its pro-apoptotic function. In mice infected with lymphocytic choriomeningitis virus (LCMV), Trail deficiency led to improved specific CD8+ T-cell responses, resulting in faster pathogen clearance and reduced liver pathology. Depletion experiments indicated that this effect was mediated by NK cells. Mechanistically, TRAIL expressed by immune cells positively and dose-dependently modulates IL-15 signaling-induced granzyme B production in NK cells, leading to enhanced NK cell-mediated T cell killing. TRAIL also regulates the signaling downstream of IL-15 receptor in human NK cells. In addition, TRAIL restricts NK1.1-triggered IFNγ production by NK cells. Our study reveals a hitherto unappreciated immunoregulatory role of TRAIL signaling on NK cells for the granzyme B-dependent elimination of antiviral T cells.",

keywords = "CD8 T cells, IL-15 signaling, NK cells, TNF-related apoptosis-inducing ligand, lymphocytic choriomeningitis virus",

author = "{Cardoso Alves}, Ludmila and Berger, {Michael D.} and Thodoris Koutsandreas and Nick Kirschke and Christoph Lauer and Roman Sp{\"o}rri and Aristotelis Chatziioannou and Nadia Corazza and Philippe Krebs",

note = "Funding Information: We thank Regula Stuber for her excellent technical support. We are grateful to Annette Oxenius (ETH Zurich, Switzerland) and Eva Szegezdi (NUI, Galway, Ireland) for providing us with reagents and to Vladimir Benes (GeneCore, Heidelberg, Germany) for advice on RNA isolation methods. We also like to extend our gratitude toward Haifeng C. Xu, Werner Held, Stefan Freigang, Daniel L. Popkin, Antoine Mar{\c c}ais, Christian M. Sch{\"u}rch, Mario Noti, and Lukas F. Mager for advice or critical comments. This work was supported by grants from the Swiss National Science Foundation (310030_138188 and 314730_163086), the “Vontobel Stiftung”, the “Olga Mayenfisch Stiftung”, the “Kurt und Senta Herrmann?Stiftung”, a generous donor advised by CARIGEST SA, the Bern University Research Foundation (all to P.K.). This project has also received funding from the European Union Seventh Framework Program (FP7) under grant agreement No PCIG12-GA-2012-334081 (X-talk) (to P.K.) and the European Union's Horizon 2020 research and innovation program under the Marie Sk?odowska-Curie grant agreement No 777995 (DISCOVER) (to P.K. and A.C.). Funding Information: We thank Regula Stuber for her excellent technical support. We are grateful to Annette Oxenius (ETH Zurich, Switzerland) and Eva Szegezdi (NUI, Galway, Ireland) for providing us with reagents and to Vladimir Benes (GeneCore, Heidelberg, Germany) for advice on RNA isolation methods. We also like to extend our gratitude toward Haifeng C. Xu, Werner Held, Stefan Freigang, Daniel L. Popkin, Antoine Mar{\c c}ais, Christian M. Sch{\"u}rch, Mario Noti, and Lukas F. Mager for advice or critical comments. This work was supported by grants from the Swiss National Science Foundation (310030_138188 and 314730_163086), the “Vontobel Stiftung”, the “Olga Mayenfisch Stiftung”, the “Kurt und Senta Herrmann?Stiftung”, a generous donor advised by CARIGEST SA, the Bern University Research Foundation (all to P.K.). This project has also received funding from the European Union Seventh Framework Program (FP7) under grant agreement No PCIG12‐GA‐2012‐334081 (X‐talk) (to P.K.) and the European Union's Horizon 2020 research and innovation program under the Marie Sk?odowska‐Curie grant agreement No 777995 (DISCOVER) (to P.K. and A.C.). Publisher Copyright: {\textcopyright} 2019 The Authors. Published under the terms of the CC BY 4.0 license",

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language = "American English",

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AU - Cardoso Alves, Ludmila

AU - Berger, Michael D.

AU - Koutsandreas, Thodoris

AU - Kirschke, Nick

AU - Lauer, Christoph

AU - Spörri, Roman

AU - Chatziioannou, Aristotelis

AU - Corazza, Nadia

AU - Krebs, Philippe

N1 - Funding Information: We thank Regula Stuber for her excellent technical support. We are grateful to Annette Oxenius (ETH Zurich, Switzerland) and Eva Szegezdi (NUI, Galway, Ireland) for providing us with reagents and to Vladimir Benes (GeneCore, Heidelberg, Germany) for advice on RNA isolation methods. We also like to extend our gratitude toward Haifeng C. Xu, Werner Held, Stefan Freigang, Daniel L. Popkin, Antoine Marçais, Christian M. Schürch, Mario Noti, and Lukas F. Mager for advice or critical comments. This work was supported by grants from the Swiss National Science Foundation (310030_138188 and 314730_163086), the “Vontobel Stiftung”, the “Olga Mayenfisch Stiftung”, the “Kurt und Senta Herrmann?Stiftung”, a generous donor advised by CARIGEST SA, the Bern University Research Foundation (all to P.K.). This project has also received funding from the European Union Seventh Framework Program (FP7) under grant agreement No PCIG12-GA-2012-334081 (X-talk) (to P.K.) and the European Union's Horizon 2020 research and innovation program under the Marie Sk?odowska-Curie grant agreement No 777995 (DISCOVER) (to P.K. and A.C.). Funding Information: We thank Regula Stuber for her excellent technical support. We are grateful to Annette Oxenius (ETH Zurich, Switzerland) and Eva Szegezdi (NUI, Galway, Ireland) for providing us with reagents and to Vladimir Benes (GeneCore, Heidelberg, Germany) for advice on RNA isolation methods. We also like to extend our gratitude toward Haifeng C. Xu, Werner Held, Stefan Freigang, Daniel L. Popkin, Antoine Marçais, Christian M. Schürch, Mario Noti, and Lukas F. Mager for advice or critical comments. This work was supported by grants from the Swiss National Science Foundation (310030_138188 and 314730_163086), the “Vontobel Stiftung”, the “Olga Mayenfisch Stiftung”, the “Kurt und Senta Herrmann?Stiftung”, a generous donor advised by CARIGEST SA, the Bern University Research Foundation (all to P.K.). This project has also received funding from the European Union Seventh Framework Program (FP7) under grant agreement No PCIG12‐GA‐2012‐334081 (X‐talk) (to P.K.) and the European Union's Horizon 2020 research and innovation program under the Marie Sk?odowska‐Curie grant agreement No 777995 (DISCOVER) (to P.K. and A.C.). Publisher Copyright: © 2019 The Authors. Published under the terms of the CC BY 4.0 license

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N2 - The role of death receptor signaling for pathogen control and infection-associated pathogenesis is multifaceted and controversial. Here, we show that during viral infection, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) modulates NK cell activity independently of its pro-apoptotic function. In mice infected with lymphocytic choriomeningitis virus (LCMV), Trail deficiency led to improved specific CD8+ T-cell responses, resulting in faster pathogen clearance and reduced liver pathology. Depletion experiments indicated that this effect was mediated by NK cells. Mechanistically, TRAIL expressed by immune cells positively and dose-dependently modulates IL-15 signaling-induced granzyme B production in NK cells, leading to enhanced NK cell-mediated T cell killing. TRAIL also regulates the signaling downstream of IL-15 receptor in human NK cells. In addition, TRAIL restricts NK1.1-triggered IFNγ production by NK cells. Our study reveals a hitherto unappreciated immunoregulatory role of TRAIL signaling on NK cells for the granzyme B-dependent elimination of antiviral T cells.

AB - The role of death receptor signaling for pathogen control and infection-associated pathogenesis is multifaceted and controversial. Here, we show that during viral infection, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) modulates NK cell activity independently of its pro-apoptotic function. In mice infected with lymphocytic choriomeningitis virus (LCMV), Trail deficiency led to improved specific CD8+ T-cell responses, resulting in faster pathogen clearance and reduced liver pathology. Depletion experiments indicated that this effect was mediated by NK cells. Mechanistically, TRAIL expressed by immune cells positively and dose-dependently modulates IL-15 signaling-induced granzyme B production in NK cells, leading to enhanced NK cell-mediated T cell killing. TRAIL also regulates the signaling downstream of IL-15 receptor in human NK cells. In addition, TRAIL restricts NK1.1-triggered IFNγ production by NK cells. Our study reveals a hitherto unappreciated immunoregulatory role of TRAIL signaling on NK cells for the granzyme B-dependent elimination of antiviral T cells.

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Non-apoptotic TRAIL function modulates NK cell activity during viral infection

Abstract

Bibliographical note

Keywords

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