The deubiquitinase Otub1 controls the activation of CD8+ T cells and NK cells by regulating IL-15-mediated priming

Xiaofei Zhou; Jiayi Yu; Xuhong Cheng; Baoyu Zhao; Ganiraju C Manyam; Li Zhang; Kimberly Schluns; Pingwei Li; Jing Wang; Shao-Cong Sun

doi:10.1038/s41590-019-0405-2

The deubiquitinase Otub1 controls the activation of CD8⁺ T cells and NK cells by regulating IL-15-mediated priming

Nat Immunol. 2019 Jul;20(7):879-889. doi: 10.1038/s41590-019-0405-2. Epub 2019 Jun 10.

Authors

Xiaofei Zhou¹, Jiayi Yu^{1

2}, Xuhong Cheng¹, Baoyu Zhao³, Ganiraju C Manyam⁴, Li Zhang^{4

5}, Kimberly Schluns^{1

6}, Pingwei Li³, Jing Wang^{4

6}, Shao-Cong Sun^{7

8}

Affiliations

¹ Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Therapeutic Tumor Microenvironment Strategies, Pittsburgh, PA, USA.
³ Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
⁴ Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA.
⁶ University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.
⁷ Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
⁸ University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA. [email protected].

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism*
Cell Differentiation / genetics
Cell Differentiation / immunology
Cysteine Endopeptidases / deficiency
Cysteine Endopeptidases / metabolism*
Deubiquitinating Enzymes / metabolism
Disease Models, Animal
Energy Metabolism
Host-Pathogen Interactions / genetics
Host-Pathogen Interactions / immunology
Humans
Interleukin-15 / genetics
Interleukin-15 / metabolism*
Killer Cells, Natural / immunology*
Killer Cells, Natural / metabolism*
Lymphocyte Activation / genetics*
Lymphocyte Activation / immunology*
Melanoma, Experimental
Mice
Mice, Transgenic
Protein Binding
Proto-Oncogene Proteins c-akt / metabolism
Receptors, Interleukin-15 / metabolism
Self Tolerance / genetics
Self Tolerance / immunology
Signal Transduction
T-Cell Antigen Receptor Specificity
Ubiquitination

Substances

Interleukin-15
Receptors, Interleukin-15
Proto-Oncogene Proteins c-akt
Deubiquitinating Enzymes
Cysteine Endopeptidases
Otub1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding