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  • Michael L Dustin
Michael L Dustin

Michael L Dustin
University of Oxford | OX · Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS)

PhD

About

663
Publications
83,801
Reads
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69,053
Citations
Additional affiliations
July 2013 - February 2016
University of Oxford
Position
  • Head of Immunology
June 1993 - December 2000
Washington University in St. Louis
Position
  • Professor (Associate)
Description
  • Headed a lab in the Clinical Science Research Building under Steve Teitelbaum and Emil Unanue.
January 2001 - present
NYU Langone Medical Center
Position
  • Resarch Professor (Part Time)

Publications

Publications (663)
Article
Full-text available
Pancreatic ductal adenocarcinoma has a dismal prognosis. A comprehensive analysis of single-cell multi-omic data from matched tumour-infiltrated CD45+ cells and peripheral blood in 12 patients, and two published datasets, reveals a complex immune infiltrate. Patients have either a myeloid-enriched or adaptive-enriched tumour microenvironment. Adapt...
Article
Cytotoxic attack particles released by CTLs and NK cells include diverse phospholipid membrane and glycoprotein encapsulated entities that contribute to target cell killing. Supramolecular attack particles (SMAPs) are one type of particle characterized by a cytotoxic core enriched in granzymes and perforin surrounded by a proteinaceous shell includ...
Preprint
Full-text available
Targeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including the critical IL-6/STAT3 axis, thereby effectively targeting different aspects of the pathological process. However, despite their clinical efficacy, a subset of RA patients r...
Article
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Immunological tolerance is a fundamental arm of any functioning immune system. Not only does tolerance mitigate collateral damage from host immune responses, but in doing so permits a robust response sufficient to clear infection as necessary. Yet, despite occupying such a cornerstone, research aiming to unravel the intricacies of tolerance inducti...
Preprint
Full-text available
CD4 T helper cells (TH cells) play a vital role in coordinating and amplifying the immune response to specific pathogens. They constitutively produce different kinds of extracellular vesicles (EVs), which mediate cell-to cell communication and play diverse roles in immune regulation and inflammatory processes. Here we provide a resource documenting...
Article
Microbial mimicry, the process in which a microbial antigen elicits an immune response and breaks tolerance to a structurally related self-antigen, has long been proposed as a mechanism in autoimmunity. In this issue of the JCI, Dolton et al. extend this paradigm by demonstrating that a naturally processed peptide from Klebsiella oxytoca acts as a...
Article
Full-text available
Cells crucially rely on the interactions of biomolecules at their plasma membrane to maintain homeostasis. Yet, a methodology to systematically quantify biomolecular organisation, measuring diffusion dynamics and oligomerisation, represents an unmet need. Here, we introduce the brightness-transit statistics (BTS) method based on fluorescence fluctu...
Preprint
Full-text available
Interleukin 2 (IL2) promotes T cell proliferation and differentiation, making it a central target in immunotherapies. T cells fine-tune their sensitivity to and consumption of IL2 by regulating surface expression and composition of the IL2 receptor. Following antigen recognition, IL2 receptor signalling is shared through polarized interactions in T...
Article
During chronic infection, virus-specific CD8⁺ cytotoxic T lymphocytes (CTLs) progressively lose their ability to mount effective antiviral responses. This “exhaustion” is coupled to persistent upregulation of inhibitory receptor programmed death-1 (PD-1) (Pdcd1)—key in suppressing antiviral CTL responses. Here, we investigate allelic Pdcd1 subnucle...
Article
CD8+ T cells contribute to immune responses by producing cytokines when their T cell receptors (TCRs) recognise peptide antigens on major-histocompability-complex (pMHC) class I. However, excessive cytokine production can be harmful. For example, cytokine release syndrome (CRS) is a common toxicity observed in treatments that activate T cells, incl...
Article
Full-text available
Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumour microenvironment, serving diverse functions in tumour progression. However, the mechanisms via which CAFs influence the anti-tumour immunity remain poorly understood. Here, using multiple tumour models and biopsies from cancer patients, w...
Article
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The expansion of T cells ex vivo is crucial for effective immunotherapy but currently limited by a lack of expansion approaches that closely mimic in vivo T cell activation. Taking inspiration from bottom‐up synthetic biology, a new synthetic cell technology is introduced based on dispersed liquid‐liquid phase‐separated droplet‐supported lipid bila...
Preprint
Full-text available
To discriminate between our own cells and foreign cells such as a pathogen, natural killer cells are armed with inhibitory and activating immune receptors. In some cases, such as the KIRs, these are found in pairs, with inhibitory and activating receptors containing nearly identical extracellular domains that are coupled to different intracellular...
Preprint
Full-text available
Supramolecular Attack Particles (SMAPs) are particulate entities, characterized by a cytotoxic core enriched in granzymes and perforin surrounded by a glycoproteic shell, released by CTLs and NK cells. Prior proteomic analysis identified thrombospondin-1 (TSP-1) and thrombospondin-4 (TSP-4) as putative components of SMAPs. While TSP-1 has been vali...
Article
Full-text available
Semaphorin-3A (SEMA3A) functions as a chemorepulsive signal during development and can affect T cells by altering their filamentous actin (F-actin) cytoskeleton. The exact extent of these effects on tumour-specific T cells are not completely understood. Here we demonstrate that Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 are upregulated on stim...
Article
Full-text available
Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103⁺ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated...
Article
Chimeric Antigen Receptor (CAR) T cell immunotherapy represents a breakthrough in the treatment of hematological malignancies. However, the rarity of cell surface protein targets that are specific to cancerous but not vital healthy tissue has hindered its broad application to solid tumor treatment. While new logic-gated CAR designs have shown reduc...
Article
Full-text available
Programmed cell death-1 (PD-1) is a potent immune checkpoint receptor on T lymphocytes. Upon engagement by its ligands, PD-L1 or PD-L2, PD-1 inhibits T cell activation and can promote immune tolerance. Antagonism of PD-1 signaling has proven effective in cancer immunotherapy, and conversely, agonists of the receptor may have a role in treating auto...
Article
In circulation, T cells are spherical with selectin enriched dynamic microvilli protruding from the surface. Following extravasation, these microvilli serve another role, continuously surveying their environment for antigen in the form of peptide‐MHC (pMHC) expressed on the surface of antigen presenting cells (APCs). Upon recognition of their cogna...
Preprint
Full-text available
CD8+ T cells contribute to immune responses by producing cytokines when their T cell receptors (TCRs) recognise peptide antigens on major-histocompability-complex (pMHC) class I. However, excessive cytokine production can be harmful. For example, cytokine release syndrome (CRS) is a common toxicity observed in treatments that activate T cells, incl...
Preprint
Full-text available
T cell immunity is impaired during ageing, particularly in memory responses needed for efficient vaccination. Autophagy and asymmetric cell division (ACD) are cell biological mechanisms key to memory formation, which undergo a decline upon ageing. However, despite the fundamental importance of these processes in cellular function, the link between...
Preprint
Full-text available
Phosphatases of regenerating liver (PRLs) have been proposed to regulate actin dynamics in lymphoid cells. However, the mechanism mediating this role remained unknown. Here we showed the interaction of the PRLs with the actin regulator WD repeat containing protein 1 (WDR1). The interaction of the PRLs with WDR1 was dependent on F-actin integrity an...
Preprint
Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumor microenvironment, serving diverse functions in tumor progression, invasion, matrix remodeling and resistance to therapy; yet, the precise mechanisms via which CAFs imprint on the anti-tumor immunity remain poorly understood. Extensive mole...
Article
Understanding cellular decisions due to receptor–ligand interactions at cell–cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the...
Article
Chimeric Antigen Receptor (CAR) T cell immunotherapy represents a conceptual breakthrough in the treatment of hematological malignancies. However, the rarity of cell surface protein targets specific to cancerous but not vital tissue has hindered its broad application to solid tumor treatment. While new logic-gated CAR designs have shown reduced tox...
Article
Full-text available
Lymphocyte-specific protein tyrosine kinase (LCK) is essential for T cell antigen receptor (TCR)–mediated signal transduction. Here, we report two siblings homozygous for a novel LCK variant (c.1318C>T; P440S) characterized by T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarr...
Article
Full-text available
An unresolved issue in contemporary biomedicine is the overwhelming number and diversity of complex images that require annotation, analysis and interpretation. Recent advances in Deep Learning have revolutionized the field of computer vision, creating algorithms that compete with human experts in image segmentation tasks. However, these frameworks...
Preprint
Full-text available
Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. Understanding the multiple mechanisms by which the tumour evades immune control, and how these mechanisms may be disrupted is critical to developing targeted immunotherapies. Previous studies have shown that higher lymphocyte infiltration is associated with better survival, an...
Preprint
Full-text available
Receptor/ligand interactions at cellular interfaces are ubiquitous and the integrated signals from multiple interactions determines cellular decision-making. However, our understanding of cell-cell recognition is hampered by the inherent difficulty in precisely controlling the density of cell-surface ligands. Here, we adapt the protein Spycatcher,...
Article
Important signaling events at the immunological synapse have increasingly been linked to cis interactions between receptors on T cells. In this issue of Immunity, Zhao et al.1 implicate cis CD28/B7 interactions facilitated by curved membrane invaginations in boosting tumor immunity.
Article
The aim of this study was to assess the L-type amino acid transporter-1 (LAT1) as a possible therapeutic target for rheumatoid arthritis (RA). Synovial LAT1 expression in RA was monitored by immunohistochemistry and transcriptomic datasets. The contribution of LAT1 to gene expression and immune synapse formation was assessed by RNA-sequencing and t...
Article
Full-text available
Germinal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription...
Article
Full-text available
CD8+ T lymphocytes play vital roles in killing infected or deranged host cells, recruiting innate immune cells, and regulating other aspects of immune responses. Like any other cell, CD8+ T cells also produce extracellular particles. These include extracellular vesicles (EVs) and non‐vesicular extracellular particles (NVEPs). T cell‐derived EVs are...
Article
Full-text available
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer and has a 5-year survival of less than 8% owing to its complex biology. As PDAC is refractory to immunotherapy, we need to understand the functional dynamics of T cells in the PDAC microenvironment to develop alternative therapeutic strategies. In this study, we performe...
Preprint
Full-text available
An unresolved issue in contemporary biomedicine is the overwhelming number and diversity of complex images that require annotation, analysis and interpretation. Recent advances in Deep Learning have revolutionized the field of computer vision, creating algorithms that compete with human experts in image segmentation tasks. Crucially however, these...
Article
Full-text available
Ligation of T cell receptor (TCR) to peptide-MHC (pMHC) complexes initiates signaling leading to T cell activation and TCR ubiquitination. Ubiquitinated TCR is then either internalized by the T cell or released toward the antigen-presenting cell (APC) in extracellular vesicles. How these distinct fates are orchestrated is unknown. Here, we show tha...
Article
Full-text available
The sensitivity of the αβ T cell receptor (TCR) is enhanced by the coreceptors CD4 and CD8αβ, which are expressed primarily by cells of the helper and cytotoxic T cell lineages, respectively. The coreceptors bind to major histocompatibility complex (MHC) molecules and associate intracellularly with the Src-family kinase Lck, which catalyzes TCR pho...
Article
Full-text available
T cells are critically important for host defense against infections. T cell activation is specific because signal initiation requires T cell receptor (TCR) recognition of foreign antigen peptides presented by major histocompatibility complexes (pMHC) on antigen presenting cells (APCs). Recent advances reveal that the TCR acts as a mechanoreceptor,...
Chapter
All forms of life need to be able to simultaneously cooperate with other life forms in their environment, while defending themselves from harmful interactions, such as infection or parasitism. The physical and chemical mechanisms that have evolved to negotiate these interactions constitute the immune system of an organism. The immune system can be...
Article
Full-text available
The common view is that T lymphocytes activate telomerase to delay senescence. Here we show that some T cells (primarily naïve and central memory cells) elongated telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs) independently of telomerase action. Upon contact with these T cells, APCs degraded shelterin to donate telome...
Preprint
The sensitivity of the αβ T-cell receptor (TCR) is enhanced by the coreceptors CD4 and CD8αβ, which are expressed primarily by cells of the helper and cytotoxic T-cell lineages, respectively. The coreceptors bind to major histocompatibility complex (MHC) molecules and associate intracellularly with the Src-family kinase Lck, which catalyzes TCR pho...
Preprint
Bispecific T-cell engagers (TcEs) link T cell receptors to tumor-associated antigens on cancer cells, forming cytotoxic immunological synapses (IS). Close membrane-to-membrane contact (≤13 nm) has been proposed as a key mechanism of TcE function. To investigate this and identify potential additional mechanisms, we compared four immunoglobulin G1-ba...
Article
Full-text available
The immunological synapse is a molecular hub that facilitates the delivery of three activation signals, namely antigen, costimulation/corepression and cytokines, from antigen-presenting cells (APC) to T cells. T cells release a fourth class of signaling entities, trans-synaptic vesicles (tSV), to mediate bidirectional communication. Here we present...
Article
Full-text available
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...
Article
Full-text available
T follicular helper (TFH) cells promote expansion of germinal center (GC) B cells and plasma cell differentiation. Whether cognate peptide-MHCII (pMHCII) density instructs selection and cell fate decisions in a quantitative manner remains unclear. Using aDEC205-OVA to differentially deliver OVA peptides to GC B cells on the basis of DEC205 allelic...
Article
Although cognate peptide-MHCII (pMHCII) is critical for B cell selection in the germinal center (GC), it is unclear how cell intrinsic differences in peptide levels contribute to selection and cell fate decisions. Here, we applied the a-DEC205-OVA (dec) model system, to deliver different levels of OVA peptide to GC B cells in situ in order to inter...
Article
Full-text available
Significance 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 t...
Article
‘Popeye, the Sailor’ cartoons taught children that eating spinach boosts strength and helps defend against bullies. Lötscher and colleagues report that dietary deficiency of magnesium ions (Mg²⁺), against which eating spinach is an excellent antidote, impairs the activity of a key adhesion molecule, LFA-1, and hinders the ability of CD8⁺ T cells to...
Article
Full-text available
Cytotoxic T lymphocytes (CTL) kill malignant and infected cells through the directed release of cytotoxic proteins into the immunological synapse (IS). The cytotoxic protein granzyme B (GzmB) is released in its soluble form or in supramolecular attack particles (SMAP). We utilize synaptobrevin2-mRFP knock-in mice to isolate fusogenic cytotoxic gran...
Article
Full-text available
In this issue of JEM, Shakiba et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20201966) tell a tale of three tumor infiltrating lymphocytes (TILs). The first TIL was too strong and became exhausted. The second TIL was too weak and became inert. The third TIL lost CD8, and this made it just right.
Article
Full-text available
MT1-MMP promotes cancer invasion by degrading barrier ECM at the leading edge, and its localization is carried out by direct vesicle transport of MT1-MMP containing vesicles along the microtubule. We identified KIF3A, KIF13A, and KIF9 as kinesins involved in MT1-MMP-containing vesicle trafficking in HT1080 cells. KIF3A and KIF13A transport MT1-MMP-...
Preprint
Full-text available
Ligation of the T cell receptor (TCR) to peptide-MHC complexes initiates signaling leading to T cell activation. Regulation of T cell responses also requires mechanisms to stop this signaling and to downregulate surface expression of the receptor. T cells achieve this both by TCR internalization and by releasing TCR loaded vesicles directly from th...
Article
Full-text available
Hematopoietic stem and progenitor cells (HSPCs) use specialized adhesive structures referred to as magnupodium to stay in hematopoietic niches. Bessey et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.202005085) define new characteristics of the magnupodium, including centriole polarization and the necessary and sufficient role of CXCR4 signal...
Article
With continuous T cell receptor (TCR) signaling, T cells can attenuate subsequent antigen responses through adaptive tolerance, thus averting autoimmunity, but potentially also providing refuge to developing cancers. Elliot and coworkers add to our understanding of adaptation via immune checkpoints by exploiting accelerated in vivo adaptive toleran...
Article
Full-text available
T-cells engage with antigen-presenting cells in search for antigenic peptides and form transient interfaces termed immunological synapses. Synapse topography affects receptor binding rates and the mutual segregation of proteins due to size exclusion effects. It is hence important to determine the 3D topography of the immunological synapse at high p...
Article
Full-text available
Small immunoglobulin superfamily (sIGSF) adhesion complexes form a corolla of microdomains around an integrin ring and secretory core during immunological synapse (IS) formation. The corolla recruits and retains major costimulatory/checkpoint complexes, like CD28, making forces that govern corolla formation of particular interest. Here, we investig...
Article
Components of the intraflagellar transport (IFT) system that regulates the assembly of the primary cilium are co-opted by the non-ciliated T cell to orchestrate polarized endosome recycling and to sustain signaling during immune synapse formation. Here, we investigated the potential role of Bardet–Biedl syndrome 1 protein (BBS1), an essential core...
Article
Full-text available
The mechanism of T cell antigen receptor (TCR-CD3) signaling remains elusive. Here, we identify mutations in the transmembrane region of TCRβ or CD3ζ that augment peptide T cell antigen receptor (pMHC)-induced signaling not explicable by enhanced ligand binding, lateral diffusion, clustering, or co-receptor function. Using a biochemical assay and m...
Article
Full-text available
The Jurkat E6.1 clone has been extensively used as a powerful tool for the genetic and biochemical dissection of the TCR signaling pathway. More recently, these cells have been exploited in imaging studies to identify key players in immunological synapse (IS) assembly in superantigen-specific conjugates and to track the dynamics of signaling molecu...
Article
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Background: The leukaemia-derived Jurkat E6.1 cell line has been used as a model T cell in the study of many aspects of T cell biology, most notably activation in response to T cell receptor (TCR) engagement. Methods: We present whole-transcriptome RNA-Sequencing data for Jurkat E6.1 cells in the resting state and two hours post-activation via TCR...
Preprint
The T cell Immunological Synapse (IS) is a pivotal hub for the regulation of adaptive immunity by endowing the exchange of information between cells engaged in physical contacts. Beyond the integration of antigen (signal one), co-stimulation (signal two), and cytokines (signal three), the IS facilitates the delivery of T-cell effector assemblies in...
Article
Full-text available
T cells use their T-cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity non-self pMHC antigens. Although the discriminatory power of the TCR is widely believed to be near-perfect, technical difficulties have hampered efforts to precisely quantify it. Here, we describe a method for measuring very low TCR/pMHC affini...