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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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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.

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/.

References

  1. Durgeau, A., Virk, Y., Corgnac, S. & Mami-Chouaib, F. Recent advances in targeting CD8 T-cell immunity for more effective cancer immunotherapy. Front. Immunol. 9, 14 (2018).

    Article  Google Scholar 

  2. Chiossone, L., Dumas, P. Y., Vienne, M. & Vivier, E. Natural killer cells and other innate lymphoid cells in cancer. Nat. Rev. Immunol. 18, 671–688 (2018).

    Article  CAS  Google Scholar 

  3. Crouse, J., Xu, H. C., Lang, P. A. & Oxenius, A. NK cells regulating T cell responses: mechanisms and outcome. Trends Immunol. 36, 49–58 (2015).

    Article  CAS  Google Scholar 

  4. Rosenberg, J. & Huang, J. CD8+ T cells and NK cells: parallel and complementary soldiers of immunotherapy. Curr. Opin. Chem. Eng. 19, 9–20 (2018).

    Article  Google Scholar 

  5. Surh, C. D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848–862 (2008).

    Article  CAS  Google Scholar 

  6. Castillo, E. F. & Schluns, K. S. Regulating the immune system via IL-15 transpresentation. Cytokine 59, 479–490 (2012).

    Article  CAS  Google Scholar 

  7. Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat. Immunol. 1, 426–432 (2000).

    Article  CAS  Google Scholar 

  8. Schluns, K. S. & Lefrancois, L. Cytokine control of memory T-cell development and survival. Nat. Rev. Immunol. 3, 269–279 (2003).

    Article  CAS  Google Scholar 

  9. Liu, K., Catalfamo, M., Li, Y., Henkart, P. A. & Weng, N. P. IL-15 mimics T cell receptor crosslinking in the induction of cellular proliferation, gene expression, and cytotoxicity in CD8+ memory T cells. Proc. Natl Acad. Sci. USA 99, 6192–6197 (2002).

    Article  CAS  Google Scholar 

  10. Deshpande, P. et al. IL-7- and IL-15-mediated TCR sensitization enables T cell responses to self-antigens. J. Immunol. 190, 1416–1423 (2013).

    Article  CAS  Google Scholar 

  11. Teague, R. M. et al. Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat. Med. 12, 335–341 (2006).

    Article  CAS  Google Scholar 

  12. Hu, H. & Sun, S. C. Ubiquitin signaling in immune responses. Cell Res. 26, 457–483 (2016).

    Article  CAS  Google Scholar 

  13. Sun, S. C. Deubiquitylation and regulation of the immune response. Nat. Rev. Immunol. 8, 501–511 (2008).

    Article  CAS  Google Scholar 

  14. Juang, Y. C. et al. OTUB1 co-opts Lys48-linked ubiquitin recognition to suppress E2 enzyme function. Mol. Cell 45, 384–397 (2012).

    Article  CAS  Google Scholar 

  15. Nakada, S. et al. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature 466, 941–946 (2010).

    Article  CAS  Google Scholar 

  16. Wang, T. et al. Evidence for bidentate substrate binding as the basis for the K48 linkage specificity of otubain 1. J. Mol. Biol. 386, 1011–1023 (2009).

    Article  CAS  Google Scholar 

  17. Wiener, R., Zhang, X., Wang, T. & Wolberger, C. The mechanism of OTUB1-mediated inhibition of ubiquitination. Nature 483, 618–622 (2012).

    Article  CAS  Google Scholar 

  18. Gubser, P. M. et al. Rapid effector function of memory CD8+ T cells requires an immediate–early glycolytic switch. Nat. Immunol. 14, 1064–1072 (2013).

    Article  CAS  Google Scholar 

  19. Kim, E. H. & Suresh, M. Role of PI3K/Akt signaling in memory CD8 T cell differentiation. Front. Immunol. 4, 20 (2013).

    PubMed  PubMed Central  Google Scholar 

  20. Cammann, C. et al. Early changes in the metabolic profile of activated CD8+ T cells. BMC Cell Biol. 17, 28 (2016).

    Article  Google Scholar 

  21. Hogquist, K. A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).

    Article  CAS  Google Scholar 

  22. Lodolce, J. P., Burkett, P. R., Koka, R. M., Boone, D. L. & Ma, A. Regulation of lymphoid homeostasis by interleukin-15. Cytokine Growth Factor Rev. 13, 429–439 (2002).

    Article  CAS  Google Scholar 

  23. Burkett, P. R. et al. IL-15Rα expression on CD8+ T cells is dispensable for T cell memory. Proc. Natl Acad. Sci. USA 100, 4724–4729 (2003).

    Article  CAS  Google Scholar 

  24. Schluns, K. S. et al. Distinct cell types control lymphoid subset development by means of IL-15 and IL-15 receptor α expression. Proc. Natl Acad. Sci. USA 101, 5616–5621 (2004).

    Article  CAS  Google Scholar 

  25. Goldrath, A. W. et al. Cytokine requirements for acute and basal homeostatic proliferation of naive and memory CD8+ T cells. J. Exp. Med. 195, 1515–1522 (2002).

    Article  CAS  Google Scholar 

  26. Guillerey, C., Huntington, N. D. & Smyth, M. J. Targeting natural killer cells in cancer immunotherapy. Nat. Immunol. 17, 1025–1036 (2016).

    Article  CAS  Google Scholar 

  27. Chiossone, L. et al. Maturation of mouse NK cells is a 4-stage developmental program. Blood 113, 5488–5496 (2009).

    Article  CAS  Google Scholar 

  28. Polansky, J. K. et al. High dose CD11c-driven IL15 is sufficient to drive NK cell maturation and anti-tumor activity in a trans-presentation independent manner. Sci. Rep. 6, 19699 (2016).

    Article  CAS  Google Scholar 

  29. Bottcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 (2018).

    Article  CAS  Google Scholar 

  30. Vadlakonda, L., Dash, A., Pasupuleti, M., Anil Kumar, K. & Reddanna, P. The paradox of Akt–mTOR interactions. Front. Oncol. 3, 165 (2013).

    PubMed  PubMed Central  Google Scholar 

  31. Kim, E. H. et al. Signal integration by Akt regulates CD8 T cell effector and memory differentiation. J. Immunol. 188, 4305–4314 (2012).

    Article  CAS  Google Scholar 

  32. Waldmann, T. A. The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunol. Res. 3, 219–227 (2015).

    Article  CAS  Google Scholar 

  33. Jethwa, N. et al. Endomembrane PtdIns(3,4,5)P3 activates the PI3K–Akt pathway. J. Cell Sci. 128, 3456–3465 (2015).

    Article  CAS  Google Scholar 

  34. Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 296, 1655–1657 (2002).

    Article  CAS  Google Scholar 

  35. Carnero, A., Blanco-Aparicio, C., Renner, O., Link, W. & Leal, J. F. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr. Cancer Drug Targets 8, 187–198 (2008).

    Article  CAS  Google Scholar 

  36. Balakirev, M. Y., Tcherniuk, S. O., Jaquinod, M. & Chroboczek, J. Otubains: a new family of cysteine proteases in the ubiquitin pathway. EMBO Rep. 4, 517–522 (2003).

    Article  CAS  Google Scholar 

  37. Yang, W. L. et al. The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science 325, 1134–1138 (2009).

    Article  CAS  Google Scholar 

  38. Calleja, V., Laguerre, M., Parker, P. J. & Larijani, B. Role of a novel PH–kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition. PLoS Biol. 7, e17 (2009).

    Article  Google Scholar 

  39. Roberts, D. J. & Miyamoto, S. Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. Cell Death Differ. 22, 248–257 (2015).

    Article  CAS  Google Scholar 

  40. Pearce, E. L., Poffenberger, M. C., Chang, C. H. & Jones, R. G. Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454 (2013).

    Article  Google Scholar 

  41. Zheng, Y., Delgoffe, G. M., Meyer, C. F., Chan, W. & Powell, J. D. Anergic T cells are metabolically anergic. J. Immunol. 183, 6095–6101 (2009).

    Article  CAS  Google Scholar 

  42. McKinney, E. F. & Smith, K. G. C. Metabolic exhaustion in infection, cancer and autoimmunity. Nat. Immunol. 19, 213–221 (2018).

    Article  CAS  Google Scholar 

  43. Huang, P. L. et al. Skeletal muscle interleukin 15 promotes CD8+ T-cell function and autoimmune myositis. Skelet. Muscle 5, 33 (2015).

    Article  Google Scholar 

  44. Overwijk, W. W. et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J. Exp. Med. 198, 569–580 (2003).

    Article  CAS  Google Scholar 

  45. Zhang, P., Cote, A. L., de Vries, V. C., Usherwood, E. J. & Turk, M. J. Induction of postsurgical tumor immunity and T-cell memory by a poorly immunogenic tumor. Cancer Res. 67, 6468–6476 (2007).

    Article  CAS  Google Scholar 

  46. Maueroder, C. et al. Tumor immunotherapy: lessons from autoimmunity. Front. Immunol. 5, 212 (2014).

    PubMed  PubMed Central  Google Scholar 

  47. Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281 (2012).

    Article  CAS  Google Scholar 

  48. Mishra, A., Sullivan, L. & Caligiuri, M. A. Molecular pathways: interleukin-15 signaling in health and in cancer. Clin. Cancer Res. 20, 2044–2050 (2014).

    Article  CAS  Google Scholar 

  49. Dubois, S., Mariner, J., Waldmann, T. A. & Tagaya, Y. IL-15Rα recycles and presents IL-15 in trans to neighboring cells. Immunity 17, 537–547 (2002).

    Article  CAS  Google Scholar 

  50. Yu, J. et al. Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation. Nat. Commun. 6, 6074 (2015).

    Article  CAS  Google Scholar 

  51. Pearce, E. L. & Shen, H. Generation of CD8 T cell memory is regulated by IL-12. J. Immunol. 179, 2074–2081 (2007).

    Article  CAS  Google Scholar 

  52. Reiley, W. W. et al. Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J. Exp. Med. 204, 1475–1485 (2007).

    Article  CAS  Google Scholar 

  53. Xiao, G., Harhaj, E. W. & Sun, S. C. NF-κB-inducing kinase regulates the processing of NF-κB2 p100. Mol. Cell. 7, 401–409 (2001).

    Article  CAS  Google Scholar 

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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.

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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.

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Correspondence to Shao-Cong Sun.

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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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Zhou, X., Yu, J., Cheng, X. et al. The deubiquitinase Otub1 controls the activation of CD8+ T cells and NK cells by regulating IL-15-mediated priming. Nat Immunol 20, 879–889 (2019). https://doi.org/10.1038/s41590-019-0405-2

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