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Molecular design of the γδ T cell receptor ectodomain encodes biologically fit ligand recognition in the absence of mechanosensing

ABSTRACT: Molecular design of the γδ T cell receptor ectodomain encodes biologically fit ligand recognition in the absence of mechanosensing

PROVIDER: PRJNA694033 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13505327_1.fastq.gz	Fastqsanger.gz
	SRR13505327_2.fastq.gz	Fastqsanger.gz
	SRR13505328_1.fastq.gz	Fastqsanger.gz
	SRR13505328_2.fastq.gz	Fastqsanger.gz
	SRR13505329_1.fastq.gz	Fastqsanger.gz

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Molecular design of the γδ T cell receptor ectodomain encodes biologically fit ligand recognition in the absence of mechanosensing

Project description:High acuity αβT cell receptor (TCR) recognition of peptides bound to MHC molecules (pMHC) requires mechanosensing, a process whereby piconewton (pN) bioforces exert physical load on αβTCR-pMHC bonds to dynamically alter their lifetimes and foster digital sensitivity cellular signaling. While mechanotransduction is operative for both αβTCRs and preTCRs within the αβT-lineage, its role in γδT cells is unknown. Here we show that the human DP10.7 γδTCR specific for the sulfoglycolipid sulfatide bound to CD1d only sustains significant load and undergoes force-induced structural transitions when the binding interface-distal γδ constant domain (C) module is replaced with that of αβ. The chimeric γδ-αβTCR also signals more robustly than the wild-type γδTCR as revealed by RNA-seq analysis of TCR-transduced Rag2-/- thymocytes, consistent with structural, single molecule and molecular dynamics studies reflective of γδTCRs as mediating recognition via a more canonical immunoglobulin-like receptor interaction. Absence of robust, force-related catch bonds as well as γδTCR structural transitions implies that γδT cells do not use mechanosensing for ligand recognition. This distinction is consonant with the fact that their innate-type ligands, including markers of cellular stress, are expressed at high copy number relative to sparse pMHC ligands of αβT cells arrayed on activating target cells. We posit that mechanosensing emerged over ~200 million years of vertebrate evolution to fulfill indispensable adaptive immune recognition requirements for pMHC in the αβT cell lineage that are unnecessary for the γδ T cell lineage mechanism of non-pMHC ligand detection.

2021-06-22 | GSE165297 | GEO

Molecular design of the γδT cell receptor ectodomain encodes biologically fit ligand recognition in the absence of mechanosensing.

Project description:High-acuity αβT cell receptor (TCR) recognition of peptides bound to major histocompatibility complex molecules (pMHCs) requires mechanosensing, a process whereby piconewton (pN) bioforces exert physical load on αβTCR-pMHC bonds to dynamically alter their lifetimes and foster digital sensitivity cellular signaling. While mechanotransduction is operative for both αβTCRs and pre-TCRs within the αβT lineage, its role in γδT cells is unknown. Here, we show that the human DP10.7 γδTCR specific for the sulfoglycolipid sulfatide bound to CD1d only sustains a significant load and undergoes force-induced structural transitions when the binding interface-distal γδ constant domain (C) module is replaced with that of αβ. The chimeric γδ-αβTCR also signals more robustly than does the wild-type (WT) γδTCR, as revealed by RNA-sequencing (RNA-seq) analysis of TCR-transduced Rag2-/- thymocytes, consistent with structural, single-molecule, and molecular dynamics studies reflective of γδTCRs as mediating recognition via a more canonical immunoglobulin-like receptor interaction. Absence of robust, force-related catch bonds, as well as γδTCR structural transitions, implies that γδT cells do not use mechanosensing for ligand recognition. This distinction is consonant with the fact that their innate-type ligands, including markers of cellular stress, are expressed at a high copy number relative to the sparse pMHC ligands of αβT cells arrayed on activating target cells. We posit that mechanosensing emerged over ∼200 million years of vertebrate evolution to fulfill indispensable adaptive immune recognition requirements for pMHC in the αβT cell lineage that are unnecessary for the γδT cell lineage mechanism of non-pMHC ligand detection.

| S-EPMC8256041 | biostudies-literature

Mechanosensing

Project description:On the significance of mechanosensing for seed development and maturation

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Fe-FIT-Diff

Project description:au13-06_fit - Fe-FIT-Diff - FIT (FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR) is a regulator of Fe deficiency responses in the root. FIT is a basic helix-loop-helix protein. Here, we investigated the transcriptome changes in response to Fe deficiency (- Fe) versus the control condition (+ Fe) in wild type, the fit-3 loss of function mutant and in FIT overexpression plants.

2015-02-14 | GSE65934 | GEO

JAG1-NOTCH4 mechanosensing drives atherosclerosis

Project description:JAG1-NOTCH4 mechanosensing drives atherosclerosis

| PRJNA849228 | ENA

fe-fit-diff_6d-Differential gene expression in A. thaliana roots depending on iron supply and FIT (FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR) abundance

Project description:au15-01_iron-fit - fe-fit-diff_6d - Changes in gene expression profiles between fit knock-out, wild-type and FIT overexpressor seedlings under sufficient iron supply and under iron deficiency. - Col-0, HA-FIT and fit-3.

2016-07-01 | GSE80281 | GEO

fe-fit-diff_6d-Differential gene expression in A. thaliana roots depending on iron supply and FIT (FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR) abundance

2016-07-01 | E-GEOD-80281 | biostudies-arrayexpress

Expression data from FIT-039 or Flavopiridol compound treated HeLa cells

Project description:FIT-039 is a novel antiviral compound. Antiviral mechanism of FIT-039 is the inhibition of the viral transcription through suppression of the CTD phosphorylation of RNA polymerase II. We used microarrays to evaluated the effect of FIT-039 on host cellular transcriptome, compared with Flavopiridol which is an existing pan-specific CDK9 inhibitor. HeLa cells were incubated with FIT-039 or flavopiridol at the concentration of IC80 for 24 hr, and cellular RNAs were collected and subjected to microarray analysis. The solvent DMSO was used as a negative control.

2014-07-08 | E-GEOD-57429 | biostudies-arrayexpress

Expression data from FIT-039 or Flavopiridol compound treated HeLa cells

2014-07-08 | GSE57429 | GEO

Demonstration of increased biologically active CXCL12Î± plasma concentrations after ACKR3 antagonist treatment in humans

Project description:CXCL12 is a chemokine that binds to its cognate receptors CXCR4 and ACKR3 (CXCR7). An increase in CXCL12 concentrations has been used as a pharmacodynamic biomarker to assess ACKR3 antagonism in healthy adults. Furthermore, increased CXCL12 concentrations have been observed in various human pathologies. To date, CXCL12 concentrations have typically been quantified using antibody-based assays with overlapping or unclear specificity for the various existing CXCL12 proteoforms. Only the N-terminal full-length CXCL12 proteoform is biologically active and can engage CXCR4 and ACKR3. However, this proteoform could so far not be quantified in healthy adults. Here, we describe a new and validated fit-for-purpose immunoaffinity mass spectrometry (IA-MS) biomarker assay for specific measurement of five CXCL12Î± proteoforms in human plasma, including the biologically active CXCL12Î± proteoform. The assay was employed in a Phase 1 clinical study with the ACKR3 antagonist ACT-1004-1239 to quantify CXCL12Î± proteoforms. At baseline levels, 1.00 nM total CXCL12Î± and 0.10 nM biologically active CXCL12Î± was quantified in placebo treated adults. The concentrations of both proteoforms increased up to two-fold in healthy adults following drug administration. At all doses, 10% of CXCL12Î± was biologically active and the simultaneous increase of all proteoforms suggests that a new equilibrium has been reached 24 h following dosing. Hence, this IA-MS biomarker assay can be used to specifically measure active CXCL12 proteoform concentrations in clinical trials. Specific quantification of active chemokines can support decision making in clinical trial and thus successful drug development.

2024-01-27 | PXD038814 | Pride

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