TNF Receptor-Associated Factor (TRAF) Signaling Network in CD4&lt;sup&gt;+&lt;/sup&gt; T-Lymphocytes

So, Takanori; Nagashima, Hiroyuki; Ishii, Naoto

doi:10.1620/tjem.236.139

Cited by 36 publications

(21 citation statements)

References 142 publications

(188 reference statements)

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“…TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells INTRODUCTION TNFR-associated factor 5 (TRAF5), a member of the TRAF family of cytoplasmic adaptor proteins, plays a critical role in signal transduction mediated by the TNFR superfamily and cytokine receptors (1)(2)(3)(4)(5)(6)(7)(8)(9). TRAF5 is highly expressed in hematopoietic cells, such as B and T lymphocytes, and controls important functions in lymphocytes (10)(11)(12)(13)(14)(15)(16).…”

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TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells

et al. 2020

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TNFR-associated factor 5 (TRAF5) is a cytosolic adaptor protein and functions as an inflammatory regulator. However, the in vivo function of TRAF5 remains unclear, and how TRAF5 controls inflammatory responses in the intestine is not well understood. In this study, we found that intestinal epithelial cells from Traf5 2/2 mice expressed a significantly lower level of NF-kB-regulated proinflammatory genes, such as Tnf, Il6, and Cxcl1, as early as day 3 after dextran sulfate sodium (DSS) exposure when compared with wild-type mice. The intestinal barrier integrity of DSS-treated Traf5 2/2 mice remained intact at this early time point, and Traf5 2/2 mice showed decreased body weight loss and longer colon length at later time points. Surprisingly, the protein level of TRAF2, but not TRAF3, was reduced in colon tissues of Traf5 2/2 mice after DSS, indicating the requirement of TRAF5 for TRAF2 protein stability in the inflamed colon. Experiments with bone marrow chimeras confirmed that TRAF5 deficiency in nonhematopoietic cells caused the attenuated colitis. Our in vitro experiments demonstrated that proinflammatory cytokines significantly promoted the degradation of TRAF2 protein in Traf5 2/2 nonhematopoietic cells in a proteasome-dependent manner. Collectively, our data suggest a novel regulatory function of TRAF5 in supporting the proinflammatory function of TRAF2 in nonhematopoietic cells, which may be important for acute inflammatory responses in the intestine.

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TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells

et al. 2020

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“…This suggests that optimization of TRAF recruitment to costimulatory domains can enhance CAR T cell function. TRAF proteins regulate T cell function by linking extracellular activation receptors, including 4-1BB, and intracellular signaling pathways, thereby impacting T cell differentiation, proliferation, survival, and cytokine production (36,49). TRAF proteins have been speculated as having multiple roles in transducing 4-1BB costimulation in CARs, but to date none have been able to confirm or define their specific roles (27,39).…”

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confidence: 99%

4-1BB enhancement of CAR T function requires NF-κB and TRAFs

Li¹,

Boucher²,

Kotani³

et al. 2018

JCI Insight

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Chimeric antigen receptors (CARs) have an antigen-binding domain fused to transmembrane, costimulatory, and CD3ζ domains. Two CARs with regulatory approval include a CD28 or 4-1BB costimulatory domain. While both CARs achieve similar clinical outcomes, biologic differences have become apparent but not completely understood. Therefore, in this study we aimed to identify mechanistic differences between 4-1BB and CD28 costimulation that contribute to the biologic differences between the 2 CARs and could be exploited to enhance CAR T cell function. Using CD19-targeted CAR T cells with 4-1BB we determined that enhancement of T cell function is driven by NF-κB. Comparison to CAR T cells with CD28 also revealed that 4-1BB is associated with more antiapoptotic proteins and dependence on persistence for B cell killing. While TNF receptor-associated factor 2 (TRAF2) has been presupposed to be required for 4-1BB costimulation in CAR T cells, we determined that TRAF1 and TRAF3 are also critical. We observed that TRAFs impacted CAR T viability and proliferation, as well as cytotoxicity and/or cytokines, in part by regulating NF-κB. Our study demonstrates how 4-1BB costimulation in CAR T cells impacts antitumor eradication and clinical outcomes and has implications for enhanced CAR design.

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“…The C-terminal domain of TRAFs, which is composed of a coiled-coil/leucine zipper domain (TRAF-N) followed by a TRAF domain (TRAF-C), contributes to homo-or hetero-oligomerization of TRAF proteins and their recognition of a variety of cytoplasmic and receptor proteins (9)(10)(11). There is growing evidence that TRAFs control the differentiation of CD4 + T cells (12)(13)(14)(15)(16)(17)(18)(19). We have shown that TRAF5 inhibits the differentiation of Th17 cells by antagonizing signaling via the receptor for IL-6 (18).…”

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TNFR-Associated Factors 2 and 5 Differentially Regulate the Instructive IL-6 Receptor Signaling Required for Th17 Development

Nagashima

Okuyama

Hayashi

et al. 2016

The Journal of Immunology

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IL-17–producing CD4+ T cells (Th17 cells) regulate host defense and immune pathogenesis, and IL-6 plays an important role for the differentiation of Th17 cells. We have previously identified that TNFR-associated factor (TRAF)5 binds to the signal-transducing receptor gp130 through the C-terminal TRAF domain and inhibits Th17 development mediated by IL-6. Although gp130 has TRAF-binding motifs that can be recognized by other TRAF family proteins, it is unclear how TRAFs regulate IL-6–driven Th17 differentiation in general. Using retrovirus-mediated gene complementation and gene silencing approaches, we found that not only TRAF5 but also TRAF2 restrained the IL-6R signaling, whereas TRAF1, TRAF3, TRAF4, and TRAF6 did not. Traf2 silencing further promoted the ability of naive CD4+ T cells from Traf5−/− mice to differentiate into Th17 cells. Notably, TRAF5 but not TRAF2 expressed in naive CD4+ T cells was rapidly downregulated after TCR triggering, which indicates that TRAF5 specifically inhibits instructive IL-6 signals in the initial stage of Th17 development. Collectively, our results demonstrate a dedicated role for TRAF2 and TRAF5 in the process of IL-6–mediated Th17 development and a differential role for TCR signaling in regulation of TRAF2 and TRAF5. Therefore, both TRAF2 and TRAF5 work as important regulators of the IL-6R signaling needed for Th17 development.

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TNF Receptor-Associated Factor (TRAF) Signaling Network in CD4<sup>+</sup> T-Lymphocytes

Cited by 36 publications

References 142 publications

TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells

TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells

4-1BB enhancement of CAR T function requires NF-κB and TRAFs

TNFR-Associated Factors 2 and 5 Differentially Regulate the Instructive IL-6 Receptor Signaling Required for Th17 Development

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