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T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo

The cyclin-dependent kinase 6 (CDK6) regulates the transition through the G1-phase of the cell cycle, but also acts as a transcriptional regulator. As such CDK6 regulates cell survival or cytokine secretion together with STATs, AP-1 or NF-κB. In the hematopoietic system, CDK6 regulates T cell develo...

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Autores principales: Klein, Klara, Witalisz-Siepracka, Agnieszka, Gotthardt, Dagmar, Agerer, Benedikt, Locker, Felix, Grausenburger, Reinhard, Knab, Vanessa Maria, Bergthaler, Andreas, Sexl, Veronika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264666/
https://www.ncbi.nlm.nih.gov/pubmed/34248938
http://dx.doi.org/10.3389/fimmu.2021.650977
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author Klein, Klara
Witalisz-Siepracka, Agnieszka
Gotthardt, Dagmar
Agerer, Benedikt
Locker, Felix
Grausenburger, Reinhard
Knab, Vanessa Maria
Bergthaler, Andreas
Sexl, Veronika
author_facet Klein, Klara
Witalisz-Siepracka, Agnieszka
Gotthardt, Dagmar
Agerer, Benedikt
Locker, Felix
Grausenburger, Reinhard
Knab, Vanessa Maria
Bergthaler, Andreas
Sexl, Veronika
author_sort Klein, Klara
collection PubMed
description The cyclin-dependent kinase 6 (CDK6) regulates the transition through the G1-phase of the cell cycle, but also acts as a transcriptional regulator. As such CDK6 regulates cell survival or cytokine secretion together with STATs, AP-1 or NF-κB. In the hematopoietic system, CDK6 regulates T cell development and promotes leukemia and lymphoma. CDK4/6 kinase inhibitors are FDA approved for treatment of breast cancer patients and have been reported to enhance T cell-mediated anti-tumor immunity. The involvement of CDK6 in T cell functions remains enigmatic. We here investigated the role of CDK6 in CD8+ T cells, using previously generated CDK6 knockout (Cdk6 (-/-)) and kinase-dead mutant CDK6 (Cdk6 (K43M)) knock-in mice. RNA-seq analysis indicated a role of CDK6 in T cell metabolism and interferon (IFN) signaling. To investigate whether these CDK6 functions are T cell-intrinsic, we generated a T cell-specific CDK6 knockout mouse model (Cdk6 (fl/fl) CD4-Cre). T cell-intrinsic loss of CDK6 enhanced mitochondrial respiration in CD8+ T cells, but did not impact on cytotoxicity and production of the effector cytokines IFN-γ and TNF-α by CD8+ T cells in vitro. Loss of CDK6 in peripheral T cells did not affect tumor surveillance of MC38 tumors in vivo. Similarly, while we observed an impaired induction of early responses to type I IFN in CDK6-deficient CD8+ T cells, we failed to observe any differences in the response to LCMV infection upon T cell-intrinsic loss of CDK6 in vivo. This apparent contradiction might at least partially be explained by the reduced expression of Socs1, a negative regulator of IFN signaling, in CDK6-deficient CD8+ T cells. Therefore, our data are in line with a dual role of CDK6 in IFN signaling; while CDK6 promotes early IFN responses, it is also involved in the induction of a negative feedback loop. These data assign CDK6 a role in the fine-tuning of cytokine responses.
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spelling pubmed-82646662021-07-09 T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo Klein, Klara Witalisz-Siepracka, Agnieszka Gotthardt, Dagmar Agerer, Benedikt Locker, Felix Grausenburger, Reinhard Knab, Vanessa Maria Bergthaler, Andreas Sexl, Veronika Front Immunol Immunology The cyclin-dependent kinase 6 (CDK6) regulates the transition through the G1-phase of the cell cycle, but also acts as a transcriptional regulator. As such CDK6 regulates cell survival or cytokine secretion together with STATs, AP-1 or NF-κB. In the hematopoietic system, CDK6 regulates T cell development and promotes leukemia and lymphoma. CDK4/6 kinase inhibitors are FDA approved for treatment of breast cancer patients and have been reported to enhance T cell-mediated anti-tumor immunity. The involvement of CDK6 in T cell functions remains enigmatic. We here investigated the role of CDK6 in CD8+ T cells, using previously generated CDK6 knockout (Cdk6 (-/-)) and kinase-dead mutant CDK6 (Cdk6 (K43M)) knock-in mice. RNA-seq analysis indicated a role of CDK6 in T cell metabolism and interferon (IFN) signaling. To investigate whether these CDK6 functions are T cell-intrinsic, we generated a T cell-specific CDK6 knockout mouse model (Cdk6 (fl/fl) CD4-Cre). T cell-intrinsic loss of CDK6 enhanced mitochondrial respiration in CD8+ T cells, but did not impact on cytotoxicity and production of the effector cytokines IFN-γ and TNF-α by CD8+ T cells in vitro. Loss of CDK6 in peripheral T cells did not affect tumor surveillance of MC38 tumors in vivo. Similarly, while we observed an impaired induction of early responses to type I IFN in CDK6-deficient CD8+ T cells, we failed to observe any differences in the response to LCMV infection upon T cell-intrinsic loss of CDK6 in vivo. This apparent contradiction might at least partially be explained by the reduced expression of Socs1, a negative regulator of IFN signaling, in CDK6-deficient CD8+ T cells. Therefore, our data are in line with a dual role of CDK6 in IFN signaling; while CDK6 promotes early IFN responses, it is also involved in the induction of a negative feedback loop. These data assign CDK6 a role in the fine-tuning of cytokine responses. Frontiers Media S.A. 2021-06-24 /pmc/articles/PMC8264666/ /pubmed/34248938 http://dx.doi.org/10.3389/fimmu.2021.650977 Text en Copyright © 2021 Klein, Witalisz-Siepracka, Gotthardt, Agerer, Locker, Grausenburger, Knab, Bergthaler and Sexl https://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
Klein, Klara
Witalisz-Siepracka, Agnieszka
Gotthardt, Dagmar
Agerer, Benedikt
Locker, Felix
Grausenburger, Reinhard
Knab, Vanessa Maria
Bergthaler, Andreas
Sexl, Veronika
T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo
title T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo
title_full T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo
title_fullStr T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo
title_full_unstemmed T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo
title_short T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo
title_sort t cell-intrinsic cdk6 is dispensable for anti-viral and anti-tumor responses in vivo
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264666/
https://www.ncbi.nlm.nih.gov/pubmed/34248938
http://dx.doi.org/10.3389/fimmu.2021.650977
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