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

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.

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Data availability

RNA sequencing datasets were deposited to Gene Expression Omnibus with the accession code GSE126777. Other datasets generated during the current study are available from the corresponding author upon reasonable request. The human skin cutaneous melanoma datasets reported by other studies were downloaded from http://www.oncolnc.org/.

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Acknowledgements

We thank S. Dubois (NCI/NIH) and Q. Yi (Cleveland Clinic) for cell lines and D. Durocher (Lunenfeld–Tanenbaum Research Institute) and P. Martin (University of Nice Sophia Antipolis) for plasmids. This study was supported by NIH grant AI64639 (to S.-C.S.) and partially supported by the following grants: National Institutes of Health grants AI057555 and GM84459 (to S.-C.S.), AI121458-01A1 (to K.S.) and AI145287 (to P.L.); Cancer Prevention & Research Institute of Texas grant RP160188 (to K.S.); Bridge Biotherapeutics (to S.-C.S.); Mission Therapeutics (to S.-C.S.); and Nektar Therapeutics (to K.S.). This study was also supported by NIH/NCI grant P30 CA016672 and used the flow cytometry, sequencing and microarray, and animal facility of the Cancer Center Support Grant-shared resources at the MD Anderson Cancer Center.

Author information

X.Z. designed and performed the research, prepared the figures and wrote part of the manuscript; J.Y. performed research; X.C. contributed to the generation and maintenance of Otub1fl/fl mice; G.C.M., L.Z. and J.W. contributed to the RNA sequencing data analysis; K.S., B.Z. and P. L. contributed critical reagents; and S.-C.S. supervised the work and wrote the manuscript.

Correspondence to Shao-Cong Sun.

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Competing interests

J.Y. is an employee of Therapeutic Tumor Microenvironment Strategies, and S.-C.S. received research funding from Bridge Biotherapeutics and Mission Therapeutics. The other authors declare no competing interests.

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Further reading

Fig. 1: Otub1 regulates the homeostasis and activation of CD8+ T cells.
Fig. 2: Otub1 controls IL-15-mediated homeostatic responses and priming of CD8+ T cells.
Fig. 3: Otub1 controls the maturation and activation of NK cells.
Fig. 4: Otub1 controls the AKT axis of IL-15R signaling and is localized to the membrane compartment in an IL-15-dependent manner.
Fig. 5: Otub1 inhibits K63 ubiquitination, PIP3 binding and membrane translocation of AKT.
Fig. 6: Otub1 regulates gene expression and glycolytic metabolism in activated CD8+ T cells.
Fig. 7: Otub1 deficiency promotes CD8+ T cell responses to a self-antigen.
Fig. 8: Otub1 regulates anticancer immunity.