Requirement of Treg-intrinsic CTLA4/PKCη signaling pathway for suppressing tumor immunity

Pedros, Christophe; Canonigo-Balancio, Ann J.; Kong, Kok-Fai; Altman, Amnon

doi:10.1172/jci.insight.95692

Cited by 25 publications

(25 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Impairment of Tregs and their suppressive function has been reported to promote tumor rejection (Klages et al, 2010; Kline et al, 2012; Pedros et al, 2017; Yu et al, 2018). To determine the role of Tfam in Tregs in tumor immunity, we crossed Tfam fl/fl mice with Foxp3 eGFP-Cre-ERT2 mice (whose Cre nuclear localization and subsequent gene deletion were induced by tamoxifen) to specifically and inducibly delete Tfam in Tregs and subsequently challenged the mice with B16-OVA (Figure 7D).…”

Section: Resultsmentioning

confidence: 99%

Requirement of Mitochondrial Transcription Factor A in Tissue-Resident Regulatory T Cell Maintenance and Function

Dean

et al. 2019

Cell Reports

View full text Add to dashboard Cite

SUMMARY Regulatory T cells (Tregs) are pivotal for immune suppression. Cellular metabolism is important for Treg homeostasis and function. However, the exact role of mitochondrial respiration in Tregs remains elusive. Mitochondrial transcription factor A (Tfam) is essential for mitochondrial respiration and controls mitochondrial DNA replication, transcription, and packaging. Here, we show that genetic ablation of Tfam in Tregs impairs Treg maintenance in non-lymphoid tissues in the steady state and in tumors. Tfam-deficient Tregs have reduced proliferation and Foxp3 expression upon glucose deprivation in vitro . Tfam deficiency preferentially affects gene activation in Tregs through regulation of DNA methylation, with enhanced methylation in the TSDR of the Foxp3 locus. Deletion of Tfam in Tregs affects Treg homing and stability, resulting in tissue inflammation in colitis, but enhances tumor rejection. Thus, our work reveals a critical role of Tfam-mediated mitochondrial respiration in Tregs to regulate inflammation and anti-tumor immunity.

show abstract

Section: Resultsmentioning

confidence: 99%

Requirement of Mitochondrial Transcription Factor A in Tissue-Resident Regulatory T Cell Maintenance and Function

Dean

et al. 2019

Cell Reports

View full text Add to dashboard Cite

show abstract

“…As such, it is conceivable that TRAF molecules, which can modulate TCR and CD28 signaling (see above), may potentially influence the CTLA-4-mediated regulatory pathway to modulate T cell signaling during an immune response. On the other hand, in Foxp3 + Tregs, CTLA-4 recruits the kinase PKCη to potentiate its suppressive functions in vitro and in vivo ( 126 , 127 ). The CTLA-4-PKCη complex promotes the activation of the canonical NF-κB pathway in Tregs, representing a unique positive signaling event ( 126 ).…”

Section: Molecular Interactions In T Fh Differentimentioning

confidence: 99%

Role of TRAFs in Signaling Pathways Controlling T Follicular Helper Cell Differentiation and T Cell-Dependent Antibody Responses

Pedros

Kong

2018

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

Follicular helper T (TFH) cells represent a highly specialized CD4+ T cell subpopulation that supports the generation of germinal centers (GC) and provides B cells with critical signals promoting antibody class switching, generation of high affinity antibodies, and memory formation. TFH cells are characterized by the expression of the chemokine receptor CXCR5, the transcription factor Bcl-6, costimulatory molecules ICOS, and PD-1, and the production of cytokine IL-21. The acquisition of a TFH phenotype is a complex and multistep process that involves signals received through engagement of the TCR along with a multitude of costimulatory molecules and cytokines receptors. Members of the Tumor necrosis factor Receptor Associated Factors (TRAF) represent one of the major classes of signaling mediators involved in the differentiation and functions of TFH cells. TRAF molecules are the canonical adaptor molecules that physically interact with members of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) and actively modulate their downstream signaling cascades through their adaptor function and/or E3 ubiquitin ligase activity. OX-40, GITR, and 4-1BB are the TRAF-dependent TNFRSF members that have been implicated in the differentiation and functions of TFH cells. On the other hand, emerging data demonstrate that TRAF proteins also participate in signaling from the TCR and CD28, which deliver critical signals leading to the differentiation of TFH cells. More intriguingly, we recently showed that the cytoplasmic tail of ICOS contains a conserved TANK-binding kinase 1 (TBK1)-binding motif that is shared with TBK1-binding TRAF proteins. The presence of this TRAF-mimicking signaling module downstream of ICOS is required to mediate the maturation step during TFH differentiation. In addition, JAK-STAT pathways emanating from IL-2, IL-6, IL-21, and IL-27 cytokine receptors affect TFH development, and crosstalk between TRAF-mediated pathways and the JAK-STAT pathways can contribute to generate integrated signals required to drive and sustain TFH differentiation. In this review, we will introduce the molecular interactions and the major signaling pathways controlling the differentiation of TFH cells. In each case, we will highlight the contributions of TRAF proteins to these signaling pathways. Finally, we will discuss the role of individual TRAF proteins in the regulation of T cell-dependent humoral responses.

show abstract

“…T cell receptor (TCR) activation can promote many signal transduction cascades and ultimately determine cell fate by regulating cytokine production, cell survival, proliferation, and differentiation [ 39 ]. Regulatory T (Treg) cells can weaken anti-tumor immune responses, which could serve as a promising immuno-therapeutic approach for tumors [ 40 ]. The Fc epsilon RI receptor induces multiple signaling pathways that control the secretion of allergic mediators and induction of cytokine gene transcription, resulting in secretion of various molecules: IL-4, IL-5, IL-6, IL-10, IL-13, INF-gamma (interferon-gamma), and TNF-alpha (tumor necrosis factor alpha) [ 41 ].…”

Section: Resultsmentioning

confidence: 99%

Deciphering Key Pharmacological Pathways of Qingdai Acting on Chronic Myeloid Leukemia Using a Network Pharmacology-Based Strategy

Liu

et al. 2018

Med Sci Monit

View full text Add to dashboard Cite

Qingdai, a traditional Chinese medicine (TCM) used for the treatment of chronic myeloid leukemia (CML) with good efficacy, has been used in China for decades. However, due to the complexity of traditional Chinese medicinal compounds, the pharmacological mechanism of Qingdai needs further research. In this study, we investigated the pharmacological mechanisms of Qingdai in the treatment of CML using network pharmacology approaches.First, components in Qingdai that were selected by pharmacokinetic profiles and biological activity predicted putative targets based on a combination of 2D and 3D similarity measures with known ligands. Then, an interaction network of Qingdai putative targets and known therapeutic targets for the treatment of chronic myeloid leukemia was constructed. By calculating the 4 topological features (degree, betweenness, closeness, and coreness) of each node in the network, we identified the candidate Qingdai targets according to their network topological importance. The composite compounds of Qingdai and the corresponding candidate major targets were further validated by a molecular docking simulation.Seven components in Qingdai were selected and 32 candidate Qingdai targets were identified; these were more frequently involved in cytokine-cytokine receptor interaction, cell cycle, p53 signaling pathway, MAPK signaling pathway, and immune system-related pathways, which all play important roles in the progression of CML. Finally, the molecular docking simulation showed that 23 pairs of chemical components and candidate Qingdai targets had effective binding.This network-based pharmacology study suggests that Qingdai acts through the regulation of candidate targets to interfere with CML and thus regulates the occurrence and development of CML.

show abstract

Requirement of Treg-intrinsic CTLA4/PKCη signaling pathway for suppressing tumor immunity

Cited by 25 publications

References 62 publications

Requirement of Mitochondrial Transcription Factor A in Tissue-Resident Regulatory T Cell Maintenance and Function

Requirement of Mitochondrial Transcription Factor A in Tissue-Resident Regulatory T Cell Maintenance and Function

Role of TRAFs in Signaling Pathways Controlling T Follicular Helper Cell Differentiation and T Cell-Dependent Antibody Responses

Deciphering Key Pharmacological Pathways of Qingdai Acting on Chronic Myeloid Leukemia Using a Network Pharmacology-Based Strategy

Contact Info

Product

Resources

About