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  1. Article ; Online: The interplay between membrane topology and mechanical forces in regulating T cell receptor activity

    Mohammad Ameen Al-Aghbar / Ashwin K. Jainarayanan / Michael L. Dustin / Steve R. Roffler

    Communications Biology, Vol 5, Iss 1, Pp 1-

    2022  Volume 16

    Abstract: Al-Aghbar et al propose a TCR bending mechanosignal model that demonstrates how local mechanical membrane bending may influence T cell receptor binding events and thus T-cell activation. ...

    Abstract Al-Aghbar et al propose a TCR bending mechanosignal model that demonstrates how local mechanical membrane bending may influence T cell receptor binding events and thus T-cell activation.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Germinal center expansion but not plasmablast differentiation is proportional to peptide-MHCII density via CD40-CD40L signaling strength

    Zhixin Jing / Mark J. McCarron / Michael L. Dustin / David R. Fooksman

    Cell Reports, Vol 39, Iss 5, Pp 110763- (2022)

    2022  

    Abstract: Summary: 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 ... ...

    Abstract Summary: 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 αDEC205-OVA to differentially deliver OVA peptides to GC B cells on the basis of DEC205 allelic copy number, we find DEC205+/+ B cells take up 2-fold more antigen than DEC205+/− cells, leading to proportional TFH cell help and B cell expansion. To validate these results, we establish a caged OVA peptide, which is readily detected by OVA-specific TFH cells after photo-uncaging. In situ uncaging of peptides leads to multiple serial B-T contacts and cell activation. Differential CD40 signaling, is both necessary and sufficient to mediate 2-fold differences in B cell expansion. While plasmablast numbers are increased, pMHCII density does not directly control the output or quality of plasma cells. Thus, we distinguish the roles TFH cells play in expansion versus differentiation.
    Keywords CP: Immunology ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Localizing order to boost signaling

    Štefan Bálint / Michael L Dustin

    eLife, Vol

    2017  Volume 6

    Abstract: B-cell receptors form ordered clusters to recruit kinases and exclude phosphatases. ...

    Abstract B-cell receptors form ordered clusters to recruit kinases and exclude phosphatases.
    Keywords super-resolution microscopy ; lipid raft ; membrane phase separation ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2017-03-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: RNA-Seq analysis of early transcriptional responses to activation in the leukaemic Jurkat E6.1 T cell line [version 2; peer review

    Suet Ling Felce / Michael L. Dustin / Gillian Farnie / James H. Felce

    Wellcome Open Research, Vol

    2 approved, 1 approved with reservations]

    2021  Volume 5

    Abstract: 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- ... ...

    Abstract 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 and CD28. We compare early transcriptional responses in the presence and absence of the chemokines CXCL12 and CCL19, and perform a basic comparison between observed transcriptional responses in Jurkat E6.1 cells and those in primary human T cells using publicly deposited data. Results: Jurkat E6.1 cells have many of the hallmarks of standard T cell transcriptional responses to activation, but lack most of the depth of responses in primary cells. Conclusions: These data indicate that Jurkat E6.1 cells hence represent only a highly simplified model of early T cell transcriptional responses.
    Keywords RNA-Seq ; T cell activation ; Jurkats ; Chemokines ; eng ; Medicine ; R ; Science ; Q
    Subject code 571
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Wellcome
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Coreceptors and TCR Signaling – the Strong and the Weak of It

    Alexander M. Mørch / Štefan Bálint / Ana Mafalda Santos / Simon J. Davis / Michael L. Dustin

    Frontiers in Cell and Developmental Biology, Vol

    2020  Volume 8

    Abstract: The T-cell coreceptors CD4 and CD8 have well-characterized and essential roles in thymic development, but how they contribute to immune responses in the periphery is unclear. Coreceptors strengthen T-cell responses by many orders of magnitude – beyond a ... ...

    Abstract The T-cell coreceptors CD4 and CD8 have well-characterized and essential roles in thymic development, but how they contribute to immune responses in the periphery is unclear. Coreceptors strengthen T-cell responses by many orders of magnitude – beyond a million-fold according to some estimates – but the mechanisms underlying these effects are still debated. T-cell receptor (TCR) triggering is initiated by the binding of the TCR to peptide-loaded major histocompatibility complex (pMHC) molecules on the surfaces of other cells. CD4 and CD8 are the only T-cell proteins that bind to the same pMHC ligand as the TCR, and can directly associate with the TCR-phosphorylating kinase Lck. At least three mechanisms have been proposed to explain how coreceptors so profoundly amplify TCR signaling: (1) the Lck recruitment model and (2) the pseudodimer model, both invoked to explain receptor triggering per se, and (3) two-step coreceptor recruitment to partially triggered TCRs leading to signal amplification. More recently it has been suggested that, in addition to initiating or augmenting TCR signaling, coreceptors effect antigen discrimination. But how can any of this be reconciled with TCR signaling occurring in the absence of CD4 or CD8, and with their interactions with pMHC being among the weakest specific protein-protein interactions ever described? Here, we review each theory of coreceptor function in light of the latest structural, biochemical, and functional data. We conclude that the oldest ideas are probably still the best, i.e., that their weak binding to MHC proteins and efficient association with Lck allow coreceptors to amplify weak incipient triggering of the TCR, without comprising TCR specificity.
    Keywords CD4 ; CD8 ; T-cell signaling ; TCR triggering ; antigen discrimination ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Pseudotime dynamics of T cells in pancreatic ductal adenocarcinoma inform distinct functional states within the regulatory and cytotoxic T cells

    Ashwin Jainarayanan / Nithishwer Mouroug-Anand / Edward H. Arbe-Barnes / Adam J. Bush / Rachael Bashford-Rogers / Adam Frampton / Lara Heij / Mark Middleton / Michael L. Dustin / Enas Abu-Shah / Shivan Sivakumar

    iScience, Vol 26, Iss 4, Pp 106324- (2023)

    2023  

    Abstract: Summary: 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 ... ...

    Abstract Summary: 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 performed RNA velocity-based pseudotime analysis on a scRNA-seq dataset from surgically resected human PDAC specimens to gain insight into temporal gene expression patterns that best characterize the cell fates. The tumor microenvironment was seen to encompass a range of terminal states for the T cell trajectories with suppressive and non-tumor-responsive T cells dominating them. However, the results also reveal the existence of a functional branch of the T cell population that was not transitioning to exhausted and senescent states. These findings reveal various microenvironmental signals driving T cell patterns which can be useful in identifying new therapeutic avenues.
    Keywords Immune response ; Bioinformatics ; Cancer systems biology ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2023-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Evolutionary design of explainable algorithms for biomedical image segmentation

    Kévin Cortacero / Brienne McKenzie / Sabina Müller / Roxana Khazen / Fanny Lafouresse / Gaëlle Corsaut / Nathalie Van Acker / François-Xavier Frenois / Laurence Lamant / Nicolas Meyer / Béatrice Vergier / Dennis G. Wilson / Hervé Luga / Oskar Staufer / Michael L. Dustin / Salvatore Valitutti / Sylvain Cussat-Blanc

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 18

    Abstract: Abstract 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, ... ...

    Abstract Abstract 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 require large human-annotated datasets for training and the resulting “black box” models are difficult to interpret. In this study, we introduce Kartezio, a modular Cartesian Genetic Programming-based computational strategy that generates fully transparent and easily interpretable image processing pipelines by iteratively assembling and parameterizing computer vision functions. The pipelines thus generated exhibit comparable precision to state-of-the-art Deep Learning approaches on instance segmentation tasks, while requiring drastically smaller training datasets. This Few-Shot Learning method confers tremendous flexibility, speed, and functionality to this approach. We then deploy Kartezio to solve a series of semantic and instance segmentation problems, and demonstrate its utility across diverse images ranging from multiplexed tissue histopathology images to high resolution microscopy images. While the flexibility, robustness and practical utility of Kartezio make this fully explicable evolutionary designer a potential game-changer in the field of biomedical image processing, Kartezio remains complementary and potentially auxiliary to mainstream Deep Learning approaches.
    Keywords Science ; Q
    Subject code 006 ; 004
    Language English
    Publishing date 2023-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Editorial

    Jorge Bernardino de la Serna / Mario Mellado / Michael L. Dustin / Maria F. Garcia-Parajo / Dimitrios Morikis

    Frontiers in Physics, Vol

    ImmunoPhysics and ImmunoEngineering

    2020  Volume 8

    Keywords immunophysics ; immunoengineering ; T cell biology ; biophysics ; cell membrane ; cell sensing and remodeling ; Physics ; QC1-999
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Single-cell glycolytic activity regulates membrane tension and HIV-1 fusion.

    Charles A Coomer / Irene Carlon-Andres / Maro Iliopoulou / Michael L Dustin / Ewoud B Compeer / Alex A Compton / Sergi Padilla-Parra

    PLoS Pathogens, Vol 16, Iss 2, p e

    2020  Volume 1008359

    Abstract: There has been resurgence in determining the role of host metabolism in viral infection yet deciphering how the metabolic state of single cells affects viral entry and fusion remains unknown. Here, we have developed a novel assay multiplexing genetically- ...

    Abstract There has been resurgence in determining the role of host metabolism in viral infection yet deciphering how the metabolic state of single cells affects viral entry and fusion remains unknown. Here, we have developed a novel assay multiplexing genetically-encoded biosensors with single virus tracking (SVT) to evaluate the influence of global metabolic processes on the success rate of virus entry in single cells. We found that cells with a lower ATP:ADP ratio prior to virus addition were less permissive to virus fusion and infection. These results indicated a relationship between host metabolic state and the likelihood for virus-cell fusion to occur. SVT revealed that HIV-1 virions were arrested at hemifusion in glycolytically-inactive cells. Interestingly, cells acutely treated with glycolysis inhibitor 2-deoxyglucose (2-DG) become resistant to virus infection and also display less surface membrane cholesterol. Addition of cholesterol in these in glycolytically-inactive cells rescued the virus entry block at hemifusion and enabled completion of HIV-1 fusion. Further investigation with FRET-based membrane tension and membrane order reporters revealed a link between host cell glycolytic activity and host membrane order and tension. Indeed, cells treated with 2-DG possessed lower plasma membrane lipid order and higher tension values, respectively. Our novel imaging approach that combines lifetime imaging (FLIM) and SVT revealed not only changes in plasma membrane tension at the point of viral fusion, but also that HIV is less likely to enter cells at areas of higher membrane tension. We therefore have identified a connection between host cell glycolytic activity and membrane tension that influences HIV-1 fusion in real-time at the single-virus fusion level in live cells.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Distinct behavior of myelomonocytic cells and CD8 T cells underlies the hepatic response to Listeria monocytogenes [version 1; referees

    Peter Velázquez / Cassandra Williams / Ingrid Leiner / Eric G. Pamer / Michael L. Dustin

    Wellcome Open Research, Vol

    2 approved]

    2018  Volume 3

    Abstract: Background: The immune response to Listeria monocytogenes (LM) is characterized by formation of leukocyte rich foci of infection in liver and spleen. Although much has been gained in our understanding of immune response through the study of LM, little is ...

    Abstract Background: The immune response to Listeria monocytogenes (LM) is characterized by formation of leukocyte rich foci of infection in liver and spleen. Although much has been gained in our understanding of immune response through the study of LM, little is known about spatio-temporal regulation of immune response to Listeria in liver. Methods: We utilize a combination of molecular, genetic and intravital microscopic approaches to gain insight into the dynamics of foci and leukocyte behavior during hepatic Listeriosis. Results: LM foci efficiently exclude blood flow, indicating the presence of a barrier separating the foci and healthy tissue. Despite this barrier, sinusoidal myelomonocytic cells readily enter or transiently interact with cells at the edge of foci of infection. Next, utilizing L9.6 transgenic CD8+ T cells specific for an endogenously processed LM antigen, p60 217-225, along with LM deficient in this epitope, we define the role of TCR in T cell migratory behavior in infected liver. Surprisingly, T cell behavior varies with micro-anatomic locale. Near foci, non-specific adhesion mechanisms dominate lymphocyte behavior. Antigen specific effects on motility became detectable only distal to foci. Conclusions: These data suggest that LM antigens act in a paracrine manner to mediate protection from Listeriosis in the liver.
    Keywords Bacterial Infections ; Immune Response ; Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2018-04-01T00:00:00Z
    Publisher Wellcome
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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