ORCID Profile
0000-0003-4983-6389
Current Organisations
University of Exeter
,
University of Liverpool
,
University of Essex
,
University of Oxford
,
Kennedy Institute of Rheumatology
,
Brasenose College, University of Oxford
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Publisher: Public Library of Science (PLoS)
Date: 03-10-2014
Publisher: Springer Science and Business Media LLC
Date: 23-06-2020
Publisher: Elsevier BV
Date: 11-2018
Publisher: The American Association of Immunologists
Date: 11-2014
Abstract: To determine the breadth and underpinning of changes in immunocyte gene expression due to genetic variation in mice, we performed, as part of the Immunological Genome Project, gene expression profiling for CD4+ T cells and neutrophils purified from 39 inbred strains of the Mouse Phenome Database. Considering both cell types, a large number of transcripts showed significant variation across the inbred strains, with 22% of the transcriptome varying by 2-fold or more. These included 119 loci with apparent complete loss of function, where the corresponding transcript was not expressed in some of the strains, representing a useful resource of “natural knockouts.” We identified 1222 cis-expression quantitative trait loci (cis-eQTL) that control some of this variation. Most (60%) cis-eQTLs were shared between T cells and neutrophils, but a significant portion uniquely impacted one of the cell types, suggesting cell type–specific regulatory mechanisms. Using a conditional regression algorithm, we predicted regulatory interactions between transcription factors and potential targets, and we demonstrated that these predictions overlap with regulatory interactions inferred from transcriptional changes during immunocyte differentiation. Finally, comparison of these and parallel data from CD4+ T cells of healthy humans demonstrated intriguing similarities in variability of a gene’s expression: the most variable genes tended to be the same in both species, and there was an overlap in genes subject to strong cis-acting genetic variants. We speculate that this “conservation of variation” reflects a differential constraint on intraspecies variation in expression levels of different genes, either through lower pressure for some genes, or by favoring variability for others.
Publisher: Elsevier BV
Date: 2009
Publisher: Elsevier BV
Date: 06-2004
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.4161/AUTO.19496
Publisher: Springer Science and Business Media LLC
Date: 07-09-2012
DOI: 10.1038/NRI3300
Abstract: Although the field has a long collaborative tradition, immunology has made less use than genetics of 'consortium biology', wherein groups of investigators together tackle large integrated questions or problems. However, immunology is naturally suited to large-scale integrative and systems-level approaches, owing to the multicellular and adaptive nature of the cells it encompasses. Here, we discuss the value and drawbacks of this organization of research, in the context of the long-running 'big science' debate, and consider the opportunities that may exist for the immunology community. We position this analysis in light of our own experience, both positive and negative, as participants of the Immunological Genome Project.
Publisher: Cold Spring Harbor Laboratory
Date: 27-12-2020
DOI: 10.1101/2020.12.26.424333
Abstract: Autoimmune diseases and in particular type 1 diabetes rely heavily on treatments that target the symptoms rather than prevent the underlying disease. One of the barriers to better therapeutic strategies is the inability to detect and efficiently target rare autoreactive T-cell populations that are major drivers of these conditions. Here, we develop a unique artificial antigen presenting cell (aAPC) system from biocompatible polymer particles that allows specific encapsulation of bioactive ingredients. Using our aAPC we demonstrate that we are able to detect rare autoreactive CD4 populations in human patients and using mouse models we demonstrate that our particles are able to induce desensitization in the autoreactive population. This system provides a promising tool that can be used in the prevention of autoimmunity before disease onset.
Publisher: American Chemical Society (ACS)
Date: 26-05-2022
Publisher: Cold Spring Harbor Laboratory
Date: 13-02-2020
DOI: 10.1101/2020.02.12.945170
Abstract: Protein-protein binding domains are critical in signalling networks. Src homology 2 (SH2) domains are binding domains that interact with sequences containing phosphorylated tyrosines. A subset of SH2 domain-containing proteins have tandem domains, which are thought to enhance binding affinity and specificity. However, a trade-off exists between long-lived binding and the ability to rapidly reverse signalling, which is a critical requirement of noise filtering mechanisms such as kinetic proofreading. Here, we use modelling to show that the unbinding rate of tandem, but not single, SH2 domains can be accelerated by phosphatases when tandem domains bind by a kinetic, but not a static, avidity mode. We use surface plasmon resonance to show that ZAP70, a tandem SH2 domain-containing kinase, binds kinetically to biphosphorylated peptides from the T cell antigen receptor (TCR) and that the unbinding rate can be accelerated by the phosphatase CD45. An important functional prediction of regulated unbinding is that the intracellular ZAP70/TCR half-life in T cells will be correlated to the extracellular TCR/antigen half-life and we show that this is the case in both cell lines and primary T cells. The work highlights that binding by kinetic avidity breaks the trade-off between signal fidelity (requiring long half-life) and signal reversibility (requiring short half-life), which is a key requirement for T cell antigen discriminated mediated by kinetic proofreading.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2013
DOI: 10.1038/NI.2587
Publisher: Proceedings of the National Academy of Sciences
Date: 09-08-2013
Abstract: Alternative splicing (AS) allows increased ersity and orthogonal regulation of the transcriptional products of mammalian genomes. To assess the distribution and variation of alternative splicing across cell lineages of the immune system, we comprehensively analyzed RNA sequencing and microarray data generated by the Immunological Genome Project Consortium. AS is pervasive: 60% of genes showed frequent AS isoforms in T or B lymphocytes, with 7,599 previously unreported isoforms. Distinct cell specificity was observed, with differential exon skipping in 5% of genes otherwise coexpressed in both B and T cells. The distribution of isoforms was mostly all or none, suggesting on/off switching as a frequent mode of AS regulation in lymphocytes. From the identification of differential exon use in the microarray data, clustering of exon inclusion/exclusion patterns across all Immunological Genome Project cell types showed that ∼70% of AS exons are distributed along a common pattern linked to lineage differentiation and cell cycling. Other AS events distinguished myeloid from lymphoid cells or affected only a small set of exons without clear lineage specificity (e.g., Ptprc ). Computational analysis predicted specific associations between AS exons and splicing regulators, which were verified by detection of the hnRPLL/ Ptprc connection.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2013
DOI: 10.1038/NI.2536
Publisher: Proceedings of the National Academy of Sciences
Date: 23-02-2022
Abstract: Src homology 2 (SH2) domains are phosphotyrosine binding motifs that play key roles in cellular signaling. There are 110 proteins in the human genome containing SH2 binding domains, of which 10 contain tandem SH2 domains. Tandem domains have been shown to improve avidity and specificity and contribute to allostery. Here, we show that tandem SH2 domains can also exhibit binding lifetimes that are accelerated by the activity of phosphatases. This accelerated unbinding requires tandem SH2 domains to engage their substrates in dynamic binding modes that cycle between single SH2-bound states. We experimentally confirm that this is the case for the well-studied kinase ZAP70 binding the T cell receptor. We suggest that accelerated unbinding is a general feature of signaling networks.
Publisher: Springer Science and Business Media LLC
Date: 05-05-2013
DOI: 10.1038/NI.2590
Publisher: Wiley
Date: 10-2019
Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring ex les of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion.
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Michael Dustin.