Unexpected positive control of NFκB and miR-155 by DGKα and ζ ensures effector and memory CD8+ T cell differentiation

Yang, Jialong; Zhang, Ping; Krishna, Sruti; Wang, Jinli; Lin, Xingguang; Huang, Haihong; Xie, Denghui; Gorentla, Balachandra K.; Huang, Rick H.; Gao, Jimin; Li, Qi-Jing; Zhong, Xiao‐Ping

doi:10.18632/oncotarget.8164

Cited by 27 publications

(30 citation statements)

References 74 publications

(95 reference statements)

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“…Whereas acute CD8 + T cell effector responses are enhanced in DGKζ deficient mice after infection with intracellular pathogens, persistent memory formation is impaired, most dramatically when both DGKζ and DGKα, the other isoform of DGK that metabolizes DAG downstream of the TCR in T cells, are deleted (35, 36). To determine the impact of Cbl-b deletion on memory formation in conjuction with DGKζ-deficiency, we inoculated WT, DGKζ −/− , Cbl-b −/− , and DKO mice with LCMV (strain Armstrong).…”

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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“…Although deficiency of either DGKα or ζ enhances antiviral immune responses, DGKα and ζ double deficiency actually caused severe impairment of CD8 T cell-mediated responses to Listeria monocytogenes (LM) infection (Yang et al, 2016b). In an ovalbumin (OVA) specific OT1 TCR transgenic model and newly generated floxed DGKζ conditional-deficient mice where DGKα and ζ activity can be selectively deleted in naïve and memory CD8 T cells, it was found that ablation of both DGKα and ζ, but not of the individual DGKα or ζ isoform, impaired primary CD8 T cell responses (Table 1).…”

Section: Dgkα and ζ In Cd8 T Cell-mediated Antipathogen Immune Responsesmentioning

confidence: 99%

“…In addition, DGKα and ζ double deficiency compromised memory CD8 T cell function in homeostasis. Ablation of DGKα and ζ in preformed memory CD8 T cells accelerated the decline of these cells due to increased death and decreased homeostatic proliferative renewal (Yang et al, 2016b). …”

Section: Dgkα and ζ In Cd8 T Cell-mediated Antipathogen Immune Responsesmentioning

confidence: 99%

“…In DGKα and ζ double deficient CD8 T cells, TCR-induced NFκB nuclear localization was surprisingly diminished, although nuclear NFκB was elevated before stimulation (Yang et al, 2016b). A similar situation was also observed in T cells expressing a constitutive active IKKβ.…”

Section: Dgkα and ζ In Cd8 T Cell-mediated Antipathogen Immune Responsesmentioning

confidence: 99%

“…Both DGKα and ζ have been found to regulate multiple signaling pathways downstream from the TCR (Zhong et al, 2002, 2003; Sanjuan et al, 2003; Baldanzi et al, 2011; Gharbi et al, 2011; Gorentla et al, 2011), such as the RasGRP1-Ras-Erk1/2 pathway, the PKCθ-IKK-NFκB pathway, mTOR signaling (Gorentla et al, 2011), and MAP kinase-interacting serine/threonine kinase (Mnk) 1 and 2 signaling (Gorentla et al, 2013). They control T cell development (Outram et al, 2002; Guo et al, 2008; Almena et al, 2013), activation and anergy (Zhong et al, 2003; Olenchock et al, 2006a; Zha et al, 2006; Baldanzi et al, 2011), survival (Baldanzi et al, 2011; Ruffo et al, 2016), secretion (Alonso et al, 2007, 2011; Chauveau et al, 2014), and effector function (Shin et al, 2012; Yang et al, 2016b). Besides T cells, DGKζ also regulates the development, survival, and function of mast cells (Olenchock et al, 2006b), B cells (Wheeler et al, 2013), dendritic cells and macrophages (Liu et al, 2007), osteoclasts (Zamani et al, 2015), and NK cells (Yang et al, 2016a).…”

Section: Introductionmentioning

confidence: 99%

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Diacylglycerol Kinases in T Cell Tolerance and Effector Function

Chen

Zhong

2016

Front. Cell Dev. Biol.

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Diacylglycerol kinases (DGKs) are a family of enzymes that regulate the relative levels of diacylglycerol (DAG) and phosphatidic acid (PA) in cells by phosphorylating DAG to produce PA. Both DAG and PA are important second messengers cascading T cell receptor (TCR) signal by recruiting multiple effector molecules, such as RasGRP1, PKCθ, and mTOR. Studies have revealed important physiological functions of DGKs in the regulation of receptor signaling and the development and activation of immune cells. In this review, we will focus on recent progresses in our understanding of two DGK isoforms, α and ζ, in CD8 T effector and memory cell differentiation, regulatory T cell development and function, and invariant NKT cell development and effector lineage differentiation.

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Graded diacylglycerol kinases α and ζ activities ensure mucosal‐associated invariant T‐cell development in mice

et al. 2019

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Mucosal-associated invariant T (MAIT) cells participate in both protective immunity and pathogenesis of diseases. Most murine MAIT cells express an invariant TCRVα19-Jα33(iVα19) TCR, which triggers signals crucial for their development. However, signal pathways downstream of the iVα19TCR and their regulation in MAIT cells are unknown. Diacylglycerol (DAG) is a critical second messenger that relays the TCR signal to multiple downstream signaling cascades. DAG is terminated by DAG kinase (DGK)-mediated phosphorylation and conversion to phosphatidic acid. We have demonstrated here that downregulation of DAG caused by enhanced DGK activity impairs late-stage MAIT cell maturation in both thymus and spleen. Moreover, deficiency of DGKζ but not DGKα by itself causes modest decreases in MAIT cells, and deficiency of both DGKα and ζ results in severe reductions of MAIT cells in an autonomous manner. Our studies have revealed that DAG signaling is not only critical but also must be tightly regulated by DGKs for MAIT cell development and that both DGKα and, more prominently, DGKζ contribute to the overall DGK activity for MAIT cell development.Keywords: DGKα r DGKζ r Diacylglycerol kinases r MAIT cells r Mucosal-associated invariant T cells r Signal transduction Additional supporting information may be found online in the Supporting Information section at the end of the article.

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Unexpected positive control of NFκB and miR-155 by DGKα and ζ ensures effector and memory CD8+ T cell differentiation

Cited by 27 publications

References 74 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

Diacylglycerol Kinases in T Cell Tolerance and Effector Function

Graded diacylglycerol kinases α and ζ activities ensure mucosal‐associated invariant T‐cell development in mice

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