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Diacylglycerol Kinase ζ (DGKζ) and Casitas b-Lineage Proto-Oncogene b–Deficient Mice Have Similar Functional Outcomes in T Cells but DGKζ-Deficient Mice Have Increased T Cell Activation and Tumor Clearance

Erin M. Wesley, Gang Xin, Donna McAllister, Subramaniam Malarkannan, Debra K. Newman, Michael B. Dwinell, Weiguo Cui, Bryon D. Johnson and Matthew J. Riese
ImmunoHorizons April 1, 2018, 2 (4) 107-118; DOI: https://doi.org/10.4049/immunohorizons.1700055
Erin M. Wesley
*Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226;
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Gang Xin
†Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53226;
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Donna McAllister
*Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226;
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Subramaniam Malarkannan
*Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226;
†Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53226;
‡Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226;
§Division of Hematology/Oncology/Blood and Marrow Transplant, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226; and
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Debra K. Newman
†Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53226;
¶Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226
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Michael B. Dwinell
*Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226;
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Weiguo Cui
*Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226;
†Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53226;
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Bryon D. Johnson
*Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226;
§Division of Hematology/Oncology/Blood and Marrow Transplant, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226; and
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Matthew J. Riese
*Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226;
†Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53226;
‡Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226;
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Abstract

Targeting negative regulators downstream of the TCR represents a novel strategy to improve cancer immunotherapy. Two proteins that serve as critical inhibitory regulators downstream of the TCR are diacylglycerol kinase ζ (DGKζ), a regulator of Ras and PKC-θ signaling, and Casitas b-lineage proto-oncogene b (Cbl-b), an E3 ubiquitin ligase that predominantly regulates PI(3)K signaling. We sought to compare the signaling and functional effects that result from deletion of DGKζ, Cbl-b, or both (double knockout) in T cells and to evaluate tumor responses generated in a clinically relevant orthotopic pancreatic tumor model. We found that whereas deletion of Cbl-b primarily served to enhance NF-κB signaling, deletion of DGKζ enhanced TCR-mediated signal transduction downstream of Ras/Erk and NF-κB. Deletion of DGKζ or Cbl-b comparably enhanced CD8+ T cell functional responses, such as proliferation, production of IFN-γ, and generation of granzyme B when compared with wild type T cells. Double-knockout T cells demonstrated enhanced function above that observed with single-knockout T cells after weak, but not strong, stimulation. Deletion of DGKζ, but not Cbl-b, however, resulted in significant increases in numbers of activated (CD44hi) CD8+ T cells in both nontreated and tumor-bearing mice. DGKζ-deficient mice also had enhanced control of pancreatic tumor cell growth compared with Cbl-b–deficient mice. This represents a direct comparison between mice of these genotypes and suggests that T cell immunotherapies may be better improved by targeting TCR signaling molecules that are regulated by DGKζ as opposed to molecules regulated by Cbl-b.

Footnotes

  • This work was supported by National Institutes of Health Grant K08-CA151893 (to M.J.R.) and an American Cancer Society Institutional Award (to M.J.R.).

  • Abbreviations used in this article:

    Cbl-b
    Casitas b-lineage proto-oncogene b
    DAG
    diacylglycerol
    DGKζ
    diacylglycerol kinase ζ
    DKO
    double-knockout
    DN
    double negative
    DP
    double positive
    KO
    single-knockout
    LCMV
    lymphocytic choriomeningitis virus
    Treg
    regulatory T cell
    WT
    wild type.

  • The online version of this article contains supplemental material.

  • Received October 9, 2017.
  • Accepted March 12, 2018.
  • Copyright © 2018 The Authors

This article is distributed under the terms of the CC BY 4.0 Unported license.

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ImmunoHorizons: 2 (4)
ImmunoHorizons
Vol. 2, Issue 4
1 Apr 2018
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Diacylglycerol Kinase ζ (DGKζ) and Casitas b-Lineage Proto-Oncogene b–Deficient Mice Have Similar Functional Outcomes in T Cells but DGKζ-Deficient Mice Have Increased T Cell Activation and Tumor Clearance
Erin M. Wesley, Gang Xin, Donna McAllister, Subramaniam Malarkannan, Debra K. Newman, Michael B. Dwinell, Weiguo Cui, Bryon D. Johnson, Matthew J. Riese
ImmunoHorizons April 1, 2018, 2 (4) 107-118; DOI: 10.4049/immunohorizons.1700055

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Diacylglycerol Kinase ζ (DGKζ) and Casitas b-Lineage Proto-Oncogene b–Deficient Mice Have Similar Functional Outcomes in T Cells but DGKζ-Deficient Mice Have Increased T Cell Activation and Tumor Clearance
Erin M. Wesley, Gang Xin, Donna McAllister, Subramaniam Malarkannan, Debra K. Newman, Michael B. Dwinell, Weiguo Cui, Bryon D. Johnson, Matthew J. Riese
ImmunoHorizons April 1, 2018, 2 (4) 107-118; DOI: 10.4049/immunohorizons.1700055
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