<scp>CCR</scp>
            5 deficiency impairs
            <scp>CD</scp>
            4
            <sup>+</sup>
            T‐cell memory responses and antigenic sensitivity through increased ceramide synthesis

Martín-Leal, Ana; Blanco, Raquel; Casas, Josefina; Sáez, María Eugenia; Rodríguez-Bovolenta, Elena; Rojas, Itziar de; Drechsler, Carina; Real, Luis Miguel; Fabriás, Gemma; Ruiz, Agustín; Castro, Mario; Schamel, Wolfgang W. A.; Alarcón, Balbino; Santen, Hisse M. van; Mañes, Santos

doi:10.15252/embj.2020104749

Cited by 16 publications

(24 citation statements)

References 75 publications

(103 reference statements)

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“…Considering recent reports showing that plasma lipid composition and order can alter the functional phenotype of T cells including Th cell subsets, membrane changes by ablation of very-long-acyl chain SLs might affect TCR signaling [ 47 ]. Formation of TCR oligomers at the cell surface is termed TCR nanoclusters, and recent study showed the inhibitory role of membrane ceramide in TCR nanoclustering [ 48 ]. In addition, increased CerS2 expression was correlated with the impaired TCR nanoclustering, and CerS2 silencing restored TCR nanoclustering and activation in OT-II CCR5 knockout CD4+ T cells [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells

Shin

Cho

Yoon

et al. 2021

IJMS

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(1) Background: six mammalian ceramide synthases (CerS1–6) determine the acyl chain length of sphingolipids (SLs). Although ceramide levels are increased in murine allergic asthma models and in asthmatic patients, the precise role of SLs with specific chain lengths is still unclear. The role of CerS2, which mainly synthesizes C22–C24 ceramides, was investigated in immune responses elicited by airway inflammation using CerS2 null mice. (2) Methods: asthma was induced in wild type (WT) and CerS2 null mice with ovalbumin (OVA), and inflammatory cytokines and CD4 (cluster of differentiation 4)+ T helper (Th) cell profiles were analyzed. We also compared the functional capacity of CD4+ T cells isolated from WT and CerS2 null mice. (3) Results: CerS2 null mice exhibited milder symptoms and lower Th2 responses than WT mice after OVA exposure. CerS2 null CD4+ T cells showed impaired Th2 and increased Th17 responses with concomitant higher T cell receptor (TCR) signal strength after TCR stimulation. Notably, increased Th17 responses of CerS2 null CD4+ T cells appeared only in TCR-mediated, but not in TCR-independent, treatment. (4) Conclusions: altered Th2/Th17 immune response with higher TCR signal strength was observed in CerS2 null CD4+ T cells upon TCR stimulation. CerS2 and very-long chain SLs may be therapeutic targets for Th2-related diseases such as asthma.

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Section: Discussionmentioning

confidence: 99%

Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells

Shin

Cho

Yoon

et al. 2021

IJMS

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“…By using complementary techniques, several studies have suggested that on the surface of a resting T cell, the TCR exists in a monomeric and in a nanoclustered form (Schamel et al, 2005 ; Lillemeier et al, 2010 ; Kumar et al, 2011 ; Sherman et al, 2011 ; Schamel and Alarcon, 2013 ; Pageon et al, 2016 ; Martín-Leal et al, 2020 ). Other studies only found low amount of TCR nanoclusters and thus concluded that nanoclusters would not exist (James et al, 2011 ; Rossboth et al, 2018 ).…”

Section: Cholesterol Regulates αβ Tcr Nanoclusteringmentioning

confidence: 99%

“…Likewise, the lipid ceramide reduced TCR nanoclustering (Martín-Leal et al, 2020 ). This was observed in liposomes as well as in T cells that were treated with sphingomyelinase, which hydrolyses sphingomyelin to ceramide.…”

Section: Cholesterol Regulates αβ Tcr Nanoclusteringmentioning

confidence: 99%

“…This data suggest that the cholesterol-sphingomyelin pair drives TCR nanoclustering. Interestingly, signaling by the receptor CCR5 reduces ceramide levels in antigen-experienced T cells (Martín-Leal et al, 2020 ). In these cells, along with reduced ceramide levels, increased membrane cholesterol contributes to enhanced TCR nanocluster formation and increased sensitivity of these cells compared to naive T cells.…”

Section: Cholesterol Regulates αβ Tcr Nanoclusteringmentioning

confidence: 99%

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Direct Regulation of the T Cell Antigen Receptor's Activity by Cholesterol

Pathan-Chhatbar

Drechsler

Richter

et al. 2021

Front. Cell Dev. Biol.

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Biological membranes consist of hundreds of different lipids that together with the embedded transmembrane (TM) proteins organize themselves into small nanodomains. In addition to this function of lipids, TM regions of proteins bind to lipids in a very specific manner, but the function of these TM region-lipid interactions is mostly unknown. In this review, we focus on the role of plasma membrane cholesterol, which directly binds to the αβ T cell antigen receptor (TCR), and has at least two opposing functions in αβ TCR activation. On the one hand, cholesterol binding to the TM domain of the TCRβ subunit keeps the TCR in an inactive, non-signaling conformation by stabilizing this conformation. This assures that the αβ T cell remains quiescent in the absence of antigenic peptide-MHC (the TCR's ligand) and decreases the sensitivity of the T cell toward stimulation. On the other hand, cholesterol binding to TCRβ leads to an increased formation of TCR nanoclusters, increasing the avidity of the TCRs toward the antigen, thus increasing the sensitivity of the αβ T cell. In mouse models, pharmacological increase of the cholesterol concentration in T cells caused an increase in TCR clustering, and thereby enhanced anti-tumor responses. In contrast, the γδ TCR does not bind to cholesterol and might be regulated in a different manner. The goal of this review is to put these seemingly controversial findings on the impact of cholesterol on the αβ TCR into perspective.

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“…Ceramide is an important component of the T cell receptor (TCR) signaling mechanism and pharmacological or molecular inhibition of ceramide production can impact on TCR-induced interleukin-2 production and disrupt programmed cell death (22). A recent study showed that increased synthesis of ceramide results in deficiency of C-C motif chemokine receptor 5 and weakens CD4 + T cell memory response and antigen sensitivity (23). However, the anti-tumor immune mechanism of ceramide in LUAD remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Ceramide Pathway Regulators Predict Clinical Prognostic Risk and Affect the Tumor Immune Microenvironment in Lung Adenocarcinoma

et al. 2020

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The ceramide pathway is strongly associated with the regulation of tumor proliferation, differentiation, senescence, and apoptosis. This study aimed to explore the gene signatures, prognostic value, and immune-related effects of ceramide-regulated genes in lung adenocarcinoma (LUAD). Methods: Public datasets of LUAD from The Cancer Genome Atlas and Gene Expression Omnibus were selected. Consensus clustering was adopted to classify LUAD patients, and a least absolute shrinkage and selection operator (LASSO) regression model was employed to develop a prognostic risk signature. CIBERSORT algorithm was used to estimate the association between the risk signature and the tumor immune microenvironment. Results: Most of the 22 ceramide-regulated genes were differentially expressed between LUAD and normal samples. LUAD patients were classified into two subgroups (cluster 1 and 2) and cluster 2 was associated with a poor prognosis. Furthermore, a prognostic risk signature was developed based on the three ceramide-regulated genes, Cytochrome C (CYCS), V-rel reticuloendotheliosis viral oncogene homolog A (RELA) and Fas-associated via death domain (FADD). LUAD patients with low-and high-risk scores differed concerning the subtypes of tumor−infiltrating immune cells. A moderate to weak correlation was observed between the risk score and tumor−infiltrating immune cells. Conclusions: Ceramide-regulated genes could predict clinical prognostic risk and affect the tumor immune microenvironment in LUAD.

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CCR 5 deficiency impairs CD 4 ⁺ T‐cell memory responses and antigenic sensitivity through increased ceramide synthesis

Cited by 16 publications

References 75 publications

Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells

Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells

Direct Regulation of the T Cell Antigen Receptor's Activity by Cholesterol

Ceramide Pathway Regulators Predict Clinical Prognostic Risk and Affect the Tumor Immune Microenvironment in Lung Adenocarcinoma

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CCR 5 deficiency impairs CD 4 + T‐cell memory responses and antigenic sensitivity through increased ceramide synthesis

Cited by 16 publications

References 75 publications

Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells

Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells

Direct Regulation of the T Cell Antigen Receptor's Activity by Cholesterol

Ceramide Pathway Regulators Predict Clinical Prognostic Risk and Affect the Tumor Immune Microenvironment in Lung Adenocarcinoma

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CCR 5 deficiency impairs CD 4 ⁺ T‐cell memory responses and antigenic sensitivity through increased ceramide synthesis