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STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity
Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively sp...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519029/ https://www.ncbi.nlm.nih.gov/pubmed/33042133 http://dx.doi.org/10.3389/fimmu.2020.02189 |
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author | Meissl, Katrin Simonović, Natalija Amenitsch, Lena Witalisz-Siepracka, Agnieszka Klein, Klara Lassnig, Caroline Puga, Ana Vogl, Claus Poelzl, Andrea Bosmann, Markus Dohnal, Alexander Sexl, Veronika Müller, Mathias Strobl, Birgit |
author_facet | Meissl, Katrin Simonović, Natalija Amenitsch, Lena Witalisz-Siepracka, Agnieszka Klein, Klara Lassnig, Caroline Puga, Ana Vogl, Claus Poelzl, Andrea Bosmann, Markus Dohnal, Alexander Sexl, Veronika Müller, Mathias Strobl, Birgit |
author_sort | Meissl, Katrin |
collection | PubMed |
description | Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1α and a C-terminally truncated STAT1β isoform. Aberrant splicing is frequently observed in cancer cells and several anti-cancer drugs interfere with the cellular splicing machinery. To investigate whether NK cell-mediated tumor surveillance is affected by a switch in STAT1 splicing, we made use of knock-in mice expressing either only the STAT1α (Stat1(α/α)) or the STAT1β (Stat1(β)(/)(β)) isoform. NK cells from Stat1(α/α) mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from Stat1(β/β) mice showed impaired maturation and effector functions, albeit less severe than NK cells from mice that completely lack STAT1 (Stat1(–/–)). Mechanistically, we show that NK cell maturation requires the presence of STAT1α in the niche rather than in NK cells themselves and that NK cell maturation depends on IFNγ signaling under homeostatic conditions. The impaired NK cell maturation in Stat1(β/β) mice was paralleled by decreased IL-15 receptor alpha (IL-15Rα) surface levels on dendritic cells, macrophages and monocytes. Treatment of Stat1(β/β) mice with exogenous IL-15/IL-15Rα complexes rescued NK cell maturation but not their effector functions. Collectively, our findings provide evidence that STAT1 isoforms are not functionally redundant in regulating NK cell activity and that the absence of STAT1α severely impairs, but does not abolish, NK cell-dependent tumor surveillance. |
format | Online Article Text |
id | pubmed-7519029 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-75190292020-10-09 STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity Meissl, Katrin Simonović, Natalija Amenitsch, Lena Witalisz-Siepracka, Agnieszka Klein, Klara Lassnig, Caroline Puga, Ana Vogl, Claus Poelzl, Andrea Bosmann, Markus Dohnal, Alexander Sexl, Veronika Müller, Mathias Strobl, Birgit Front Immunol Immunology Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1α and a C-terminally truncated STAT1β isoform. Aberrant splicing is frequently observed in cancer cells and several anti-cancer drugs interfere with the cellular splicing machinery. To investigate whether NK cell-mediated tumor surveillance is affected by a switch in STAT1 splicing, we made use of knock-in mice expressing either only the STAT1α (Stat1(α/α)) or the STAT1β (Stat1(β)(/)(β)) isoform. NK cells from Stat1(α/α) mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from Stat1(β/β) mice showed impaired maturation and effector functions, albeit less severe than NK cells from mice that completely lack STAT1 (Stat1(–/–)). Mechanistically, we show that NK cell maturation requires the presence of STAT1α in the niche rather than in NK cells themselves and that NK cell maturation depends on IFNγ signaling under homeostatic conditions. The impaired NK cell maturation in Stat1(β/β) mice was paralleled by decreased IL-15 receptor alpha (IL-15Rα) surface levels on dendritic cells, macrophages and monocytes. Treatment of Stat1(β/β) mice with exogenous IL-15/IL-15Rα complexes rescued NK cell maturation but not their effector functions. Collectively, our findings provide evidence that STAT1 isoforms are not functionally redundant in regulating NK cell activity and that the absence of STAT1α severely impairs, but does not abolish, NK cell-dependent tumor surveillance. Frontiers Media S.A. 2020-09-11 /pmc/articles/PMC7519029/ /pubmed/33042133 http://dx.doi.org/10.3389/fimmu.2020.02189 Text en Copyright © 2020 Meissl, Simonović, Amenitsch, Witalisz-Siepracka, Klein, Lassnig, Puga, Vogl, Poelzl, Bosmann, Dohnal, Sexl, Müller and Strobl. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Meissl, Katrin Simonović, Natalija Amenitsch, Lena Witalisz-Siepracka, Agnieszka Klein, Klara Lassnig, Caroline Puga, Ana Vogl, Claus Poelzl, Andrea Bosmann, Markus Dohnal, Alexander Sexl, Veronika Müller, Mathias Strobl, Birgit STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity |
title | STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity |
title_full | STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity |
title_fullStr | STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity |
title_full_unstemmed | STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity |
title_short | STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity |
title_sort | stat1 isoforms differentially regulate nk cell maturation and anti-tumor activity |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519029/ https://www.ncbi.nlm.nih.gov/pubmed/33042133 http://dx.doi.org/10.3389/fimmu.2020.02189 |
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