Diacylglycerol Kinase ζ Is a Target To Enhance NK Cell Function

Yang, Eun‐Ju; Singh, Brenal K.; Paustian, Amanda M. Schmidt; Kambayashi, Taku

doi:10.4049/jimmunol.1600581

Cited by 40 publications

(34 citation statements)

References 30 publications

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“…DGKζ −/− mice and T cells deficient in DGKζ are known to demonstrate enhanced clearance of tumors in subcutaneous models (12, 17, 30, 31). Similarly, Cbl-b −/− mice and T cells lacking Cbl-b demonstrate improved control of subcutaneously implanted tumors (23) and disseminated leukemia (32), along with decreased spontaneous tumor formation in ATM −/− mice (23) and ultraviolet B-treated mice (24).…”

Section: Resultsmentioning

confidence: 99%

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

Wesley

McAllister

et al. 2018

ImmunoHorizons

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Targeting negative regulators downstream of the T cell receptor (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, DKO) 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 IFNγ, and generation of granzyme B when compared with WT T cells. DKO 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 non-treated and tumor-bearing mice. DGKζ-deficient mice also had enhanced control of pancreatic tumor cell growth compared to Cbl-b-deficient mice. This represents the first 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.

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Section: Resultsmentioning

confidence: 99%

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

Wesley

McAllister

et al. 2018

ImmunoHorizons

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“…68 DGKζ-deficient mice reject tumors more efficiently in vivo . However, the mice have normal NK cell development, including inhibitory NK cell receptor expression or function.…”

Section: Other Therapeutic Checkpoints For Nk Cell Activationmentioning

confidence: 99%

Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy

Kwon

Kim

2017

Exp Mol Med

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Natural killer (NK) cells have gained considerable attention as promising therapeutic tools for cancer therapy due to their innate selectivity against cancer cells over normal healthy cells. With an array of receptors evolved to sense cellular alterations, NK cells provide early protection against cancer cells by producing cytokines and chemokines and exerting direct cytolytic activity. These effector functions are governed by signals transmitted through multiple receptor–ligand interactions but are not achieved by engaging a single activating receptor on resting NK cells. Rather, they require the co-engagement of different activating receptors that use distinct signaling modules, due to a cell-intrinsic inhibition mechanism. The redundancy of synergizing receptors and the inhibition of NK cell function by a single class of inhibitory receptor suggest the presence of common checkpoints to control NK cell activation through different receptors. These molecular checkpoints would be therapeutically targeted to harness the power of NK cells against diverse cancer cells that express heterogeneous ligands for NK cell receptors. Recent advances in understanding the activation of NK cells have revealed promising candidates in this category. Targeting such molecular checkpoints will facilitate NK cell activation by lowering activation thresholds, thereby providing therapeutic strategies that optimize NK cell reactivity against cancer.

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“…22 DGKζ deficiency also potentiates cytotoxic programs in CD8 + T and NK cells, boosting antitumor functions in an antigen-dependent 45 and -independent manner. 6,46 These and other studies CD69 is an activation marker that is induced rapidly after antigen recognition and decays very rapidly in peripheral cells. In activated CD4 T cells, CD69 expression attenuates S1P1 expression and promotes homing into the BM, where CD4 T cells evolve into memory subsets.…”

Section: Discussionmentioning

confidence: 82%

Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

Martin-Salgado¹,

Andrada

Liébana³

et al. 2020

Preprint

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Key points• DGKζ-deficiency in mice results in larger numbers of CD69-positive T cells in bone marrow, with enhanced expression of IFNγ and lytic enzymes.• DGKζ loss recapitulates many clinical aspects of human aplastic anemia, identifying a critical hub for immune system-dependent bone marrow failure. Visual abstractAbstract Acquired aplastic anemia (AA) is a rare blood disorder that results from immune-mediated destruction of bone marrow (BM) progenitor cells. Improved understanding of the mechanisms that favor T cell attack in BM could help to improve early diagnosis and disease treatment. Diacylglycerol kinase ζ (DGKζ) limits T cell responses through phosphorylation of diacylglycerol into phosphatidic acid. This reaction attenuates diacylglycerol-dependent activation of the Ras/ERK/CD69 and PKCθ/NFκB pathways in response to antigen. Here we show that, in contrast to the lack of basal activation observed in peripheral lymphoid organs, DGKζ -/mice showed increased numbers of activated T cells in BM, together with a significant increase in IFNγ as well as perforin and granzyme B and C levels. The enhanced presence of T cells in DGKζ -/mouse BM correlates with reduced BM cellularity, impaired hematopoiesis, and lower frequency of circulating red cells, granulocytes, and platelets. Our studies coincide with the recent characterization of lower DGKζ expression in T cells isolated from the BM of patients with acquired AA, and suggest that limited DGKζ expression and/or functions predispose to T cell-mediated BM destruction. This study identifies the BM as a niche particularly sensitive to DGKζ deficiency and indicates that this mouse model could be of interest for studying the mechanism that contributes to AA development.

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Diacylglycerol Kinase ζ Is a Target To Enhance NK Cell Function

Cited by 40 publications

References 30 publications

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

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

Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy

Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

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