DataSheet_1_T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo.pdf
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 (Cdk6K43M) 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 (Cdk6fl/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.
History
References
- https://doi.org//10.1128/mcb.14.3.2066
- https://doi.org//10.1038/nrc950
- https://doi.org//10.1038/onc.2015.407
- https://doi.org//10.1002/ijc.33054
- https://doi.org//10.1016/j.cell.2004.08.002
- https://doi.org//10.1158/0008-5472.CAN-08-2473
- https://doi.org//10.1182/blood-2010-08-300517
- https://doi.org//10.1016/j.ccr.2013.07.012
- https://doi.org//10.1182/blood-2014-06-584417
- https://doi.org//10.1182/blood-2015-11-683581
- https://doi.org//10.3390/ijms19123987
- https://doi.org//10.1158/2159-8290.CD-17-0912
- https://doi.org//10.1182/blood-2018-08-872648
- https://doi.org//10.1182/blood.2019003267
- https://doi.org//10.1016/j.molcel.2014.02.008
- https://doi.org//10.1016/S1470-2045%2815%2900613-0
- https://doi.org//10.1056/nejmoa1607303
- https://doi.org//10.1056/nejmoa1609709
- https://doi.org//10.1200/JCO.2017.75.6155
- https://doi.org//10.1158/0008-5472.CAN-17-2210
- https://doi.org//10.1016/j.tcb.2018.07.002
- https://doi.org//10.1177/1758835918786451
- https://doi.org//10.2147/CMAR.S250632
- https://doi.org//10.1038/nature23465
- https://doi.org//10.1158/2159-8290.CD-17-0915
- https://doi.org//10.1016/j.ccell.2018.03.023
- https://doi.org//10.1016/j.celrep.2018.02.053
- https://doi.org//10.1158/1541-7786.MCR-18-0201
- https://doi.org//10.3324/haematol.2020.256313
- https://doi.org//10.1016/S1074-7613%2801%2900227-8
- https://doi.org//10.2220/biomedres.5.19
- https://doi.org//10.1002/0471142735.im2004s43
- https://doi.org//10.4049/jimmunol.166.1.182
- https://doi.org//10.1016/j.immuni.2015.10.013
- https://doi.org//10.1016/j.ccr.2012.09.015
- https://doi.org//10.1016/j.ccr.2012.09.016
- https://doi.org//10.1038/nature22797
- https://doi.org//10.1038/s41416-020-0891-x
- https://doi.org//10.1182/bloodadvances.2020003022
- https://doi.org//10.1016/j.celrep.2015.12.094
- https://doi.org//10.1080/2162402X.2017.1314424
- https://doi.org//10.1038/s41590-019-0397-y
- https://doi.org//10.1186/s40425-019-0635-8
- https://doi.org//10.1002/0471142735.im1034s105
- https://doi.org//10.1146/annurev-immunol-042617-053019
- https://doi.org//10.1016/j.immuni.2011.12.007
- https://doi.org//10.1096/fj.202000767R
- https://doi.org//10.1016/j.cell.2013.05.016
- https://doi.org//10.1007/s002620000156
- https://doi.org//10.1182/blood-2010-06-291633
- https://doi.org//10.1007/s11248-014-9795-y
- https://doi.org//10.1371/journal.ppat.1002352
- https://doi.org//10.4049/jimmunol.174.8.4465
- https://doi.org//10.1084/jem.20050821
- https://doi.org//10.4049/jimmunol.176.8.4525
- https://doi.org//10.4049/jimmunol.1003166
- https://doi.org//10.1016/j.immuni.2014.05.003
- https://doi.org//10.1016/j.immuni.2014.05.004
- https://doi.org//10.1126/sciimmunol.aai8593
- https://doi.org//10.1016/j.immuni.2019.09.013
- https://doi.org//10.1634/stemcells.19-5-378
- https://doi.org//10.1016/j.semcdb.2008.07.010
- https://doi.org//10.4049/jimmunol.0903563
- https://doi.org//10.1074/jbc.M111.270207
- https://doi.org//10.3389/fimmu.2017.00070
- https://doi.org//10.1073/pnas.1714019114
- https://doi.org//10.1016/j.immuni.2016.10.021
- https://doi.org//10.1038/s41467-020-17441-9
- https://doi.org//10.1016/j.isci.2020.101602
- https://doi.org//10.1089/jir.2011.0028
- https://doi.org//10.1038/ni1287
- https://doi.org//10.1038/nri2093
- https://doi.org//10.4049/jimmunol.180.4.2034
- https://doi.org//10.1016/j.it.2009.09.009
Usage metrics
Read the peer-reviewed publication
Categories
- Transplantation Immunology
- Tumour Immunology
- Immunology not elsewhere classified
- Immunology
- Veterinary Immunology
- Animal Immunology
- Genetic Immunology
- Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies)
- Autoimmunity
- Cellular Immunology
- Humoural Immunology and Immunochemistry
- Immunogenetics (incl. Genetic Immunology)
- Innate Immunity