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Immunol."],"abstract":"<jats:p>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-\u03baB. 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 (<jats:italic>Cdk6<\/jats:italic><jats:sup>-\/-<\/jats:sup>) and kinase-dead mutant CDK6 (<jats:italic>Cdk6<\/jats:italic><jats:sup>K43M<\/jats:sup>) 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 (<jats:italic>Cdk6<\/jats:italic><jats:sup>fl\/fl<\/jats:sup> 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-\u03b3 and TNF-\u03b1 by CD8+ T cells <jats:italic>in vitro<\/jats:italic>. Loss of CDK6 in peripheral T cells did not affect tumor surveillance of MC38 tumors <jats:italic>in vivo<\/jats:italic>. 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 <jats:italic>in vivo<\/jats:italic>. This apparent contradiction might at least partially be explained by the reduced expression of <jats:italic>Socs1<\/jats:italic>, 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.<\/jats:p>","DOI":"10.3389\/fimmu.2021.650977","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T08:28:18Z","timestamp":1624523298000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo"],"prefix":"10.3389","volume":"12","author":[{"given":"Klara","family":"Klein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Witalisz-Siepracka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Gotthardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Agerer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Locker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Grausenburger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa 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