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

Klara Klein, Agnieszka Witalisz-Siepracka, Dagmar Gotthardt, Benedikt Agerer, Felix Locker, Reinhard Grausenburger, Vanessa Maria Knab, Andreas Bergthaler, Veronika Sexl

Research output: Journal article (peer-reviewed)Journal article

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article number650977
Pages (from-to)650977
JournalFrontiers in Immunology
Volume12
DOIs
Publication statusPublished - 24 Jun 2021

Keywords

  • Animals
  • Antiviral Agents/immunology
  • CD4-Positive T-Lymphocytes/immunology
  • CD8-Positive T-Lymphocytes/immunology
  • Cell Line
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 6/genetics
  • Cytotoxicity, Immunologic/immunology
  • Humans
  • Interferons/immunology
  • Lymphocytic choriomeningitis virus/immunology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplasms, Experimental/immunology
  • Signal Transduction/immunology

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