Zhou et al. found that IL-15 signaling in CD8+ T cells and NK cells mediates membrane recruitment of the deubiquitinase Otub1, which in turn inhibits ubiquitin-dependent activation of AKT; in this way, Otub1 acts as a negative regulator of responses to IL-15. Otub1 deficiency rendered T cells hyperresponsive to antigen stimulation, and increased CD8+ T cell effector function, survival, and glycolytic metabolism. In NK cells, Otub1 deficiency enhanced maturation and activation. Improved tumor control was observed in Otub1-deficient mice (dependent on T and NK cells) and in wild-type mice after adoptive transfer of Otub1-knockout T cells.
CD8(+) T cells and natural killer (NK) cells are central cellular components of immune responses against pathogens and cancer, which rely on interleukin (IL)-15 for homeostasis. Here we show that IL-15 also mediates homeostatic priming of CD8(+) T cells for antigen-stimulated activation, which is controlled by a deubiquitinase, Otub1. IL-15 mediates membrane recruitment of Otub1, which inhibits ubiquitin-dependent activation of AKT, a kinase that is pivotal for T cell activation and metabolism. Otub1 deficiency in mice causes aberrant responses of CD8(+) T cells to IL-15, rendering naive CD8(+) T cells hypersensitive to antigen stimulation characterized by enhanced metabolic reprograming and effector functions. Otub1 also controls the maturation and activation of NK cells. Deletion of Otub1 profoundly enhances anticancer immunity by unleashing the activity of CD8(+) T cells and NK cells. These findings suggest that Otub1 controls the activation of CD8(+) T cells and NK cells by functioning as a checkpoint of IL-15-mediated priming.
Author Info: (1) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston,
Author Info: (1) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Therapeutic Tumor Microenvironment Strategies, Pittsburgh, PA, USA. (3) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA. (5) Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA. (7) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA. (8) Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA. (9) Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA. (10) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. ssun@mdanderson.org. University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA. ssun@mdanderson.org.
