Abstract
The cytokine IL-15 mediates development and survival of immune cells, including natural killer T (NKT) cells, but the underlying mechanism of IL-15 function is incompletely understood. Here we show that IL-15 induces autophagy in NKT cells with a mechanism that involves a crucial signaling component, TBK-binding protein 1 (Tbkbp1). Tbkbp1 facilitates activation of the autophagy-initiating kinase Ulk1 through antagonizing the inhibitory action of mTORC1. This antagonization involves the recruitment of an mTORC1-opposing phosphatase to Ulk1. Tbkbp1 deficiency attenuates IL-15-stimulated NKT cell autophagy, and is associated with mitochondrial dysfunction, aberrant ROS production, defective Bcl2 expression and reduced NKT cell survival. Consequently, Tbkbp1-deficient mice have profound deficiency in NKT cells, especially IFN-γ-producing NKT1. We further show that Tbkbp1 regulates IL-15-stimulated autophagy and survival of NK cells. These findings suggest a mechanism of autophagy induction by IL-15, and establish Tbkbp1 as a regulator of NKT cell development and survival.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / immunology
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Animals
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Autophagy / genetics*
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Autophagy / immunology
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Autophagy-Related Protein-1 Homolog / genetics
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Autophagy-Related Protein-1 Homolog / immunology
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Cell Survival
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Gene Expression Regulation
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Interleukin-15 / genetics*
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Interleukin-15 / immunology
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Lymphocyte Activation
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Lymphocyte Count
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Mechanistic Target of Rapamycin Complex 1 / genetics
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Mechanistic Target of Rapamycin Complex 1 / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitochondria / immunology*
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Mitochondria / pathology
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Natural Killer T-Cells / immunology*
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Natural Killer T-Cells / pathology
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / immunology
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Reactive Oxygen Species / immunology
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Reactive Oxygen Species / metabolism
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Signal Transduction
Substances
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Adaptor Proteins, Signal Transducing
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Interleukin-15
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Proto-Oncogene Proteins c-bcl-2
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Reactive Oxygen Species
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SINTBAD protein, mouse
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Bcl2 protein, mouse
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Interferon-gamma
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Autophagy-Related Protein-1 Homolog
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Mechanistic Target of Rapamycin Complex 1
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Ulk1 protein, mouse