CD28 Inhibits T Cell Adhesion by Recruiting CAPRI to the Plasma Membrane

Strazza, Marianne; Azoulay-Alfaguter, Inbar; Dun, Bryan; Baquero-Buitrago, Jairo; Mor, Adam

doi:10.4049/jimmunol.1401492

Cited by 11 publications

(11 citation statements)

References 18 publications

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“…Both on B7.2 + anti-CD3 and B7.2•anti-CD3, the cells spread less as compared to all other cases reported. This may be related to previous reports which showed that CD28 inhibits cell spreading by acting on LFA-1 related down-stream signaling ( 55 ). Here, a similar effect seems to be operational even though LFA-1 ligands are not present.…”

Section: Discussionsupporting

confidence: 86%

T Cells on Engineered Substrates: The Impact of TCR Clustering Is Enhanced by LFA-1 Engagement

et al. 2018

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We created APC-mimetic synthetic substrates to study the impact of ligand clustering on T cell activation and spreading. The substrates exhibit antibodies directed against the TCR-complex in the form of a patterned array of sub micrometric dots surrounded by a fluid supported lipid bilayer (SLB) which may itself be functionalized with another bio-molecule. We show that for T cell adhesion mediated by T cell receptor (TCR) alone, in the patterned, but not in the corresponding homogeneous controls, the TCR, ZAP-70 and actin are present in the form of clusters or patches that co-localize with the ligand-dots. However, global cell scale parameters like cell area and actin distribution are only weakly impacted by ligand clustering. In presence of ICAM-1 - the ligand of the T cell integrin LFA-1 - on the SLB, the TCR is still clustered due to the patterning of its ligands, but now global parameters are also impacted. The actin organization changes to a peripheral ring, resembling the classical actin distribution seen on homogeneous substrates, the patterned membrane topography disappears and the membrane is flat, whereas the cell area increases significantly. These observations taken together point to a possible pivotal role for LFA-1 in amplifying the effect of TCR-clustering. No such effect is evident for co-engagement of CD28, affected via its ligand B7.2. Unlike on ICAM-1, on B7.2 cell spreading and actin organization are similar for homogeneous and patterned substrates. However, TCR and ZAP-70 clusters are still formed in the patterned case. These results indicate complementary role for LFA-1 and CD28 in the regulation and putative coupling of TCR micro-clusters to actin. The engineered substrates presented here clearly have the potential to act as platform for fundamental research in immune cell biology, as well as translational analyses in immunotherapy, for example to screen molecules for their role in T cell adhesion/activation.

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Section: Discussionsupporting

confidence: 86%

T Cells on Engineered Substrates: The Impact of TCR Clustering Is Enhanced by LFA-1 Engagement

et al. 2018

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“…This different dependence on TSP-1 is logical, since TSP-1 is proadhesive ( 19 , 21 ), and CD28 ligation should not be allowed to induce adhesion and arrest of naïve T cells searching for their cognate antigen. This assumption is supported by results showing that CD28 ligation antagonizes adhesive contacts ( 44 ).…”

Section: Co-stimulation Through Inhibition Of Lrp1-targeted Immunosupmentioning

confidence: 56%

T Cell Co-Stimulation: Inhibition of Immunosuppression?

Sundqvist

2018

Front. Immunol.

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“…RASA4 is a fetal-biased primate-specific gene that was also one of the top downregulated genes in Non-TD subjects. RASA4 is a GTPase-activating protein in the Ras signaling pathway that functions in the activation of T cells, mast cells, and macrophages [77–79]. Children with Non-TD were also observed to have downregulation of GNAO1 , encoding a G protein alpha subunit important for neurodevelopment and synaptic signaling.…”

Section: Discussionmentioning

confidence: 99%

A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood

Mordaunt¹,

Park²,

Bakulski³

et al. 2019

Molecular Autism

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BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of children in the USA. ASD risk is thought to arise from both genetic and environmental factors, with the perinatal period as a critical window. Understanding early transcriptional changes in ASD would assist in clarifying disease pathogenesis and identifying biomarkers. However, little is known about umbilical cord blood gene expression profiles in babies later diagnosed with ASD compared to non-typically developing and non-ASD (Non-TD) or typically developing (TD) children.MethodsGenome-wide transcript levels were measured by Affymetrix Human Gene 2.0 array in RNA from cord blood samples from both the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) and the Early Autism Risk Longitudinal Investigation (EARLI) high-risk pregnancy cohorts that enroll younger siblings of a child previously diagnosed with ASD. Younger siblings were diagnosed based on assessments at 36 months, and 59 ASD, 92 Non-TD, and 120 TD subjects were included. Using both differential expression analysis and weighted gene correlation network analysis, gene expression between ASD and TD, and between Non-TD and TD, was compared within each study and via meta-analysis.ResultsWhile cord blood gene expression differences comparing either ASD or Non-TD to TD did not reach genome-wide significance, 172 genes were nominally differentially expressed between ASD and TD cord blood (log2(fold change) > 0.1, p < 0.01). These genes were significantly enriched for functions in xenobiotic metabolism, chromatin regulation, and systemic lupus erythematosus (FDR q < 0.05). In contrast, 66 genes were nominally differentially expressed between Non-TD and TD, including 8 genes that were also differentially expressed in ASD. Gene coexpression modules were significantly correlated with demographic factors and cell type proportions.LimitationsASD-associated gene expression differences identified in this study are subtle, as cord blood is not the main affected tissue, it is composed of many cell types, and ASD is a heterogeneous disorder.ConclusionsThis is the first study to identify gene expression differences in cord blood specific to ASD through a meta-analysis across two prospective pregnancy cohorts. The enriched gene pathways support involvement of environmental, immune, and epigenetic mechanisms in ASD etiology.

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CD28 Inhibits T Cell Adhesion by Recruiting CAPRI to the Plasma Membrane

Cited by 11 publications

References 18 publications

T Cells on Engineered Substrates: The Impact of TCR Clustering Is Enhanced by LFA-1 Engagement

T Cells on Engineered Substrates: The Impact of TCR Clustering Is Enhanced by LFA-1 Engagement

T Cell Co-Stimulation: Inhibition of Immunosuppression?

A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood

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