A new look at T cell receptor signaling to nuclear factor-κB

Paul, Suman; Schaefer, Brian C.

doi:10.1016/j.it.2013.02.002

Cited by 112 publications

(109 citation statements)

References 126 publications

(191 reference statements)

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“…Triggering of the T cell receptor (TCR) or B cell receptor (BCR) results in the phosphorylation of the ID on specific serines (17)(18)(19)(20)(21), which neutralizes its inhibitory activity and allows the signal-induced recruitment of obligate signaling cofactors to CARD11, including Bcl10, MALT1, TRAF6, IKK␥, and caspase-8 (15). The formation and stability of the CARD11-nucleated multiprotein complex dictate the extent and duration of IKK kinase activity and NF-B activation following antigen recognition, and multiple mechanisms have been described to limit its activity (22). These include the signal-induced degradation of Bcl10 (19,(23)(24)(25)(26) and CARD11 (27) and the recruitment of the inhibitory kinesin GAKIN to CARD11, which competes for Bcl10 binding to CARD11 and modulates the CARD11 dwell time at the immunological synapse (28).…”

mentioning

confidence: 99%

Negative Regulation of CARD11 Signaling and Lymphoma Cell Survival by the E3 Ubiquitin Ligase RNF181

Pedersen

Chan

Jattani

et al. 2016

Molecular and Cellular Biology

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NF-B activation downstream of antigen receptor engagement is a highly regulated event required for lymphocyte activation during the adaptive immune response. The pathway is often dysregulated in lymphoma, leading to constitutive NF-B activity that supports the aberrant proliferation of transformed lymphocytes. To identify novel regulators of antigen receptor signaling to NF-B, we developed bioluminescence resonance energy transfer-based interaction cloning (BRIC), a screening strategy that can detect protein-protein interactions in live mammalian cells in a high-throughput manner. Using this strategy, we identified the RING finger protein RNF181 as an interactor of CARD11, a key signaling scaffold in the antigen receptor pathway. We present evidence that RNF181 functions as an E3 ubiquitin ligase to inhibit antigen receptor signaling to NF-B downstream of CARD11. The levels of the obligate signaling protein Bcl10 are reduced by RNF181 even prior to signaling, and Bcl10 can serve as a substrate for RNF181 E3 ligase activity in vitro. Furthermore, RNF181 limits the proliferation of human diffuse large B cell lymphoma cells that depend upon aberrant CARD11 signaling to NF-B for growth and survival in culture. Our results define a new regulatory checkpoint that can modulate the output of CARD11 signaling to NF-B in both normal and transformed lymphocytes.T he activation of the NF-B transcription factor downstream of antigen receptor engagement is a critical event required for lymphocyte activation during the adaptive immune response (1, 2). In humans and mice, genetic defects in components of the antigen receptor signaling pathway result in immunodeficiency syndromes in which the failure to mount an effective immune response confers enhanced susceptibilities to infection and impaired clearance of pathogens (3, 4).CARD11 is a critical signaling scaffold protein that functions to transmit signals from triggered antigen receptors to the IB kinase (IKK) complex, which inducibly phosphorylates inhibitory IB proteins, leading to their ubiquitinylation and degradation, which allows NF-B heterodimers to stably translocate to the nucleus (5-14). During antigen receptor signaling, CARD11 undergoes a transition from a closed, inactive state to an open, active scaffold that recruits several signaling cofactors into a complex that induces IKK kinase activity. CARD11 is kept inactive prior to receptor engagement by an inhibitory domain (ID) that participates in intramolecular interactions that involve the CARD, LATCH, and coiled-coil (CC) domains (15, 16). Triggering of the T cell receptor (TCR) or B cell receptor (BCR) results in the phosphorylation of the ID on specific serines (17-21), which neutralizes its inhibitory activity and allows the signal-induced recruitment of obligate signaling cofactors to CARD11, including Bcl10, MALT1, TRAF6, IKK␥, and caspase-8 (15). The formation and stability of the CARD11-nucleated multiprotein complex dictate the extent and duration of IKK kinase activity and NF-B activation following antig...

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confidence: 99%

Negative Regulation of CARD11 Signaling and Lymphoma Cell Survival by the E3 Ubiquitin Ligase RNF181

Pedersen

Chan

Jattani

et al. 2016

Molecular and Cellular Biology

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“…The CARMA1, BCL10, and MALT1 signalosome bridges TCR signaling to the IκB kinase (IKK) complex activating the canonical NF-κB pathway, which involves mainly NF-κB heterodimers consisting of RelA, c-Rel, and p50 (27). Activation of this pathway involves the ubiquitin-dependent proteasomal degradation of the IκB inhibitory proteins upon their phosphorylation at the IKK complex.…”

Section: Discussionmentioning

confidence: 99%

The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells

Giordano

Roncagalli

Bourdely

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The transcription factor NF-κB is central to inflammatory signaling and activation of innate and adaptive immune responses. Activation of the NF-κB pathway is tightly controlled by several negative feedback mechanisms, including A20, an ubiquitin-modifying enzyme encoded by the tnfaip3 gene. Mice with selective deletion of A20 in myeloid, dendritic, or B cells recapitulate some human inflammatory pathology. As we observed high expression of A20 transcripts in dysfunctional CD8 T cells in an autochthonous melanoma, we analyzed the role of A20 in regulation of CD8 T-cell functions, using mice in which A20 was selectively deleted in mature conventional T cells. These mice developed lymphadenopathy and some organ infiltration by T cells but no splenomegaly and no detectable pathology. A20-deleted CD8 T cells had increased sensitivity to antigen stimulation with production of large amounts of IL-2 and IFNγ, correlated with sustained nuclear expression of NF-κB components reticuloendotheliosis oncogene c-Rel and p65. Overexpression of A20 by retroviral transduction of CD8 T cells dampened their intratumor accumulation and antitumor activity. In contrast, relief from the A20 brake in NF-κB activation in adoptively transferred antitumor CD8 T cells led to improved control of melanoma growth. Tumor-infiltrating A20-deleted CD8 T cells had enhanced production of IFNγ and TNFα and reduced expression of the inhibitory receptor programmed cell death 1. As manipulation of A20 expression in CD8 T cells did not result in pathologic manifestations in the mice, we propose it as a candidate to be targeted to increase antitumor efficiency of adoptive T-cell immunotherapy.

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“…Next, we determined whether NFκB signaling regulates Eomes expression and T-cell survival upon infection. The role of NFκB signaling in the early steps of T-cell activation and proliferation of naïve T cells is well established (36). We reasoned that inhibiting NFκB signaling too early in the response would lead to defects in the activation and proliferation of differentiating T cells.…”

Section: Nfκb Signaling Is Required After the Peak Of The Immune Respmentioning

confidence: 99%

NFκB–Pim-1–Eomesodermin axis is critical for maintaining CD8 T-cell memory quality

Knudson

Pritzl

Saxena

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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T-cell memory is critical for long-term immunity. However, the factors involved in maintaining the persistence, function, and phenotype of the memory pool are undefined. Eomesodermin (Eomes) is required for the establishment of the memory pool. Here, we show that in T cells transitioning to memory, the expression of high levels of Eomes is not constitutive but rather requires a continuum of cell-intrinsic NFκB signaling. Failure to maintain NFκB signals after the peak of the response led to impaired Eomes expression and a defect in the maintenance of CD8 T-cell memory. Strikingly, we found that antigen receptor [T-cell receptor (TCR)] signaling regulates this process through expression of the NFκB-dependent kinase proviral integration site for Moloney murine leukemia virus-1 (PIM-1), which in turn regulates NFκB and Eomes. T cells defective in TCR-dependent NFκB signaling were impaired in late expression of Pim-1, Eomes, and CD8 memory. These defects were rescued when TCRdependent NFκB signaling was restored. We also found that NFκB-Pim-1 signals were required at memory to maintain memory CD8 T-cell longevity, effector function, and Eomes expression. Hence, an NFκB-Pim-1-Eomes axis regulates Eomes levels to maintain memory fitness.CD8 T-cell memory | NFkB | Pim-1 | Eomesodermin

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A new look at T cell receptor signaling to nuclear factor-κB

Cited by 112 publications

References 126 publications

Negative Regulation of CARD11 Signaling and Lymphoma Cell Survival by the E3 Ubiquitin Ligase RNF181

Negative Regulation of CARD11 Signaling and Lymphoma Cell Survival by the E3 Ubiquitin Ligase RNF181

The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells

NFκB–Pim-1–Eomesodermin axis is critical for maintaining CD8 T-cell memory quality

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