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459 results on '"Griffiths, Gillian M."'

1. Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy

Author

Trefny, Marcel P., Kirchhammer, Nicole, Auf der Maur, Priska, Natoli, Marina, Schmid, Dominic, Germann, Markus, Fernandez Rodriguez, Laura, Herzig, Petra, Lötscher, Jonas, Akrami, Maryam, Stinchcombe, Jane C., Stanczak, Michal A., Zingg, Andreas, Buchi, Melanie, Roux, Julien, Marone, Romina, Don, Leyla, Lardinois, Didier, Wiese, Mark, Jeker, Lukas T., Bentires-Alj, Mohamed, Rossy, Jérémie, Thommen, Daniela S., Griffiths, Gillian M., Läubli, Heinz, Hess, Christoph, and Zippelius, Alfred

Published
2023
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8. Distinct structural and catalytic roles for Zap70 in formation of the immunological synapse in CTL.

Author

Jenkins, Misty R, Stinchcombe, Jane C, Au-Yeung, Byron B, Asano, Yukako, Ritter, Alex T, Weiss, Arthur, and Griffiths, Gillian M

Subjects
Antigen-Presenting Cells, T-Lymphocytes, Cytotoxic, Cell Membrane, Animals, Mice, Inbred BALB C, Actins, ZAP-70 Protein-Tyrosine Kinase, Immunological Synapses, Gene Knockdown Techniques, Zap70, actin, immunological synapse, T-Lymphocytes, Cytotoxic, Mice, Inbred BALB C, Biochemistry and Cell Biology
Abstract

T cell receptor (TCR) activation leads to a dramatic reorganisation of both membranes and receptors as the immunological synapse forms. Using a genetic model to rapidly inhibit Zap70 catalytic activity we examined synapse formation between cytotoxic T lymphocytes and their targets. In the absence of Zap70 catalytic activity Vav-1 activation occurs and synapse formation is arrested at a stage with actin and integrin rich interdigitations forming the interface between the two cells. The membranes at the synapse are unable to flatten to provide extended contact, and Lck does not cluster to form the central supramolecular activation cluster (cSMAC). Centrosome polarisation is initiated but aborts before reaching the synapse and the granules do not polarise. Our findings reveal distinct roles for Zap70 as a structural protein regulating integrin-mediated control of actin vs its catalytic activity that regulates TCR-mediated control of actin and membrane remodelling during formation of the immunological synapse. DOI: http://dx.doi.org/10.7554/eLife.01310.001.

Published
2014

9. Loss of ARPC1B impairs cytotoxic T lymphocyte maintenance and cytolytic activity

Author

Randzavola, Lyra O., Strege, Katharina, Juzans, Marie, Asano, Yukako, Stinchcombe, Jane C., Gawden-Bone, Christian M., Seaman, Matthew N.J., Kuijpers, Taco W., and Griffiths, Gillian M.

Subjects
Becton, Dickinson and Co., Health aspects, Antigens -- Health aspects, B cells -- Health aspects, Actin -- Health aspects, Medical equipment industry -- Health aspects, Disease susceptibility -- Health aspects, Cell death -- Health aspects, Virus diseases -- Health aspects, Immune response -- Health aspects, Membrane proteins -- Health aspects, T cells -- Health aspects, Muscle proteins -- Health aspects, Cell membranes, Biochemistry, Lymphocytes, Recurrence (Disease), Proteins, Infection, Immunodeficiency
Abstract

Introduction The actin cytoskeleton coordinates a wide variety of cell functions ranging from cell division and differentiation to migration. The ability to reorganize the actin network in response to both [...], CD8 cytotoxic T lymphocytes (CTLs) rely on rapid reorganization of the branched F-actin network to drive the polarized secretion of lytic granules, initiating target cell death during the adaptive immune response. Branched F-actin is generated by the nucleation factor actin-related protein 2/3 (Arp2/3) complex. Patients with mutations in the actin-related protein complex 1B (ARPC1B) subunit of Arp2/3 show combined immunodeficiency, with symptoms of immune dysregulation, including recurrent viral infections and reduced [CD8.sup.+] T cell count. Here, we show that loss of ARPC1B led to loss of CTL cytotoxicity, with the defect arising at 2 different levels. First, ARPC1B is required for lamellipodia formation, cell migration, and actin reorganization across the immune synapse. Second, we found that ARPC1B is indispensable for the maintenance of TCR, CD8, and GLUT1 membrane proteins at the plasma membrane of CTLs, as recycling via the retromer and WASH complexes was impaired in the absence of ARPC1B. Loss of TCR, CD8, and GLUT1 gave rise to defects in T cell signaling and proliferation upon antigen stimulation of ARPC1B-deficient CTLs, leading to a progressive loss of [CD8.sup.+] T cells. This triggered an activation-induced immunodeficiency of CTL activity in ARPC1B-deficient patients, which could explain the susceptibility to severe and prolonged viral infections.

Published
2019
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10. High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation

Author

Abeler-Dörner, Lucie, Laing, Adam G., Lorenc, Anna, Ushakov, Dmitry S., Clare, Simon, Speak, Anneliese O., Duque-Correa, Maria A., White, Jacqueline K., Ramirez-Solis, Ramiro, Saran, Namita, Bull, Katherine R., Morón, Belén, Iwasaki, Jua, Barton, Philippa R., Caetano, Susana, Hng, Keng I., Cambridge, Emma, Forman, Simon, Crockford, Tanya L., Griffiths, Mark, Kane, Leanne, Harcourt, Katherine, Brandt, Cordelia, Notley, George, Babalola, Kolawole O., Warren, Jonathan, Mason, Jeremy C., Meeniga, Amrutha, Karp, Natasha A., Melvin, David, Cawthorne, Eleanor, Weinrick, Brian, Rahim, Albina, Drissler, Sibyl, Meskas, Justin, Yue, Alice, Lux, Markus, Song-Zhao, George X., Chan, Anna, Ballesteros Reviriego, Carmen, Abeler, Johannes, Wilson, Heather, Przemska-Kosicka, Agnieszka, Edmans, Matthew, Strevens, Natasha, Pasztorek, Markus, Meehan, Terrence F., Powrie, Fiona, Brinkman, Ryan, Dougan, Gordon, Jacobs, Jr, William, Lloyd, Clare M., Cornall, Richard J., Maloy, Kevin J., Grencis, Richard K., Griffiths, Gillian M., Adams, David J., and Hayday, Adrian C.

Published
2020
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11. Hedgehog Signaling Controls T Cell Killing at the Immunological Synapse

Author

de la Roche, Maike, Ritter, Alex T, Angus, Karen L, Dinsmore, Colin, Earnshaw, Charles H, Reiter, Jeremy F, and Griffiths, Gillian M

Subjects
HIV/AIDS, Cancer, Underpinning research, 1.1 Normal biological development and functioning, Inflammatory and immune system, Animals, CD8-Positive T-Lymphocytes, Cell Polarity, Cells, Cultured, Centrosome, Cytotoxicity, Immunologic, Hedgehog Proteins, Immunological Synapses, Kruppel-Like Transcription Factors, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Models, Immunological, Neuropeptides, Patched Receptors, Receptors, Antigen, T-Cell, Receptors, Cell Surface, Receptors, G-Protein-Coupled, Signal Transduction, Smoothened Receptor, T-Lymphocytes, Cytotoxic, Zinc Finger Protein GLI1, rac1 GTP-Binding Protein, General Science & Technology
Abstract

The centrosome is essential for cytotoxic T lymphocyte (CTL) function, contacting the plasma membrane and directing cytotoxic granules for secretion at the immunological synapse. Centrosome docking at the plasma membrane also occurs during cilia formation. The primary cilium, formed in nonhematopoietic cells, is essential for vertebrate Hedgehog (Hh) signaling. Lymphocytes do not form primary cilia, but we found and describe here that Hh signaling played an important role in CTL killing. T cell receptor activation, which "prearms" CTLs with cytotoxic granules, also initiated Hh signaling. Hh pathway activation occurred intracellularly and triggered Rac1 synthesis. These events "prearmed" CTLs for action by promoting the actin remodeling required for centrosome polarization and granule release. Thus, Hh signaling plays a role in CTL function, and the immunological synapse may represent a modified cilium.

Published
2013

20. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome

Author

Ammann, Sandra, Schulz, Ansgar, Krägeloh-Mann, Ingeborg, Dieckmann, Nele M.G., Niethammer, Klaus, Fuchs, Sebastian, Eckl, Katja Martina, Plank, Roswitha, Werner, Roland, Altmüller, Janine, Thiele, Holger, Nürnberg, Peter, Bank, Julia, Strauss, Anne, von Bernuth, Horst, zur Stadt, Udo, Grieve, Samantha, Griffiths, Gillian M., Lehmberg, Kai, Hennies, Hans Christian, and Ehl, Stephan

Published
2016
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22. Super-killer CTLs are generated by single gene deletion of Bach2

Author

Barton, Philippa R, Davenport, Alexander J, Hukelmann, Jens, Cantrell, Doreen A, Stinchcombe, Jane C, Richard, Arianne C, Griffiths, Gillian M, Griffiths, Gillian M [0000-0003-0434-5842], and Apollo - University of Cambridge Repository

Subjects
Cytotoxicity, Immunologic, Proteomics, Mice, Basic-Leucine Zipper Transcription Factors, Perforin, CTL, cytotoxicity, Animals, BACH2, CD8-Positive T-Lymphocytes, Gene Deletion, Granzymes, T-Lymphocytes, Cytotoxic
Abstract

Bach2 codes for a transcriptional regulator exerting major influences on T cell-mediated immune regulation. Effector CTLs derived from in vitro activation of murine CD8+ T cells showed increased proliferative and cytolytic capacity in the absence of BACH2. Before activation, BACH2-deficient splenic CD8+ T cells had a higher abundance of memory and reduced abundance of naïve cells compared to wild-type. CTLs derived from central memory T cells were more potently cytotoxic than those derived from naïve T cells, but even within separated subsets, BACH2-deficiency conferred a cytotoxic advantage. Immunofluorescence and electron microscopy revealed larger granules in BACH2-deficient compared to wild-type CTLs, and proteomic analysis showed an increase in granule content, including perforin and granzymes. Thus, the enhanced cytotoxicity observed in effector CTLs lacking BACH2 arises not only from differences in their initial differentiation state but also inherent production of enlarged cytolytic granules. These results demonstrate how a single gene deletion can produce a CTL super-killer.

Published
2022

26. Diagnosing XLP1 in patients with hemophagocytic lymphohistiocytosis

Author

Meazza, Raffaella, Tuberosa, Claudia, Cetica, Valentina, Falco, Michela, Parolini, Silvia, Grieve, Sam, Griffiths, Gillian M., Sieni, Elena, Marcenaro, Stefania, Micalizzi, Concetta, Montin, Davide, Fagioli, Franca, Moretta, Alessandro, Mingari, Maria C., Moretta, Lorenzo, Notarangelo, Luigi D., Bottino, Cristina, Aricò, Maurizio, and Pende, Daniela

Published
2014
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36. Teasing out function from morphology: Similarities between primary cilia and immune synapses

Author

Douanne, Tiphaine, Stinchcombe, Jane C, Griffiths, Gillian M, Douanne, Tiphaine [0000-0001-8197-8358], Stinchcombe, Jane C [0000-0003-1459-9299], Griffiths, Gillian M [0000-0003-0434-5842], and Apollo - University of Cambridge Repository

Subjects
Immunological Synapses, Immunology, chemical and pharmacologic phenomena, Biology, Immunological synapse, Synapse, 03 medical and health sciences, 0302 clinical medicine, Immune system, Animals, Humans, Cilia, 030304 developmental biology, 0303 health sciences, Trafficking, Cilium, Cell Biology, biochemical phenomena, metabolism, and nutrition, CTL, Centrosome, Perspective, Signal transduction, Neuroscience, 030217 neurology & neurosurgery, Function (biology), Signal Transduction, T-Lymphocytes, Cytotoxic
Abstract

Douanne et al. outline the multiple shared molecular mechanisms underlying two distinct biological structures, primary cilia and immune synapses., Immune synapses are formed between immune cells to facilitate communication and coordinate the immune response. The reorganization of receptors involved in recognition and signaling creates a transient area of plasma membrane specialized in signaling and polarized secretion. Studies on the formation of the immune synapse between cytotoxic T lymphocytes (CTLs) and their targets uncovered a critical role for centrosome polarization in CTL function and suggested a striking parallel between the synapse and primary cilium. Since these initial observations, a plethora of further morphological, functional, and molecular similarities have been identified between these two fascinating structures. In this review, we describe how advances in imaging and molecular techniques have revealed additional parallels as well as functionally significant differences and discuss how comparative studies continue to shed light on the molecular mechanisms underlying the functions of both the immune synapse and primary cilium.

Published
2021
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38. Immunodeficiency with susceptibility to lymphoma with complex genotype affecting energy metabolism (FBP1, ACAD9) and vesicle trafficking (RAB27A).

Author

Brauer, Nina, Yuto Maruta, Lisci, Miriam, Strege, Katharina, Oschlies, Ilske, Hikari Nakamura, Böhm, Svea, Lehmberg, Kai, Brandhoff, Leon, Ehl, Stephan, Parvaneh, Nima, Klapper, Wolfram, Mitsunori Fukuda, Griffiths, Gillian M., Hennies, Hans Christian, Niehues, Tim, and Ammann, Sandra

Subjects
CYTOTOXIC T cells, ENERGY metabolism, SERIAL murders, KILLER cells, LYMPHOMAS
Abstract

Introduction: Inborn errors of immunity (IEI) are characterized by a dysfunction of the immune system leading to increased susceptibility to infections, impaired immune regulation and cancer. We present a unique consanguineous family with a history of Hodgkin lymphoma, impaired EBV control and a late onset hemophagocytic lymphohistiocytosis (HLH). Methods and results: Overall, family members presented with variable impairment of NK cell and cytotoxic T cell degranulation and cytotoxicity. Exome sequencing identified homozygous variants in RAB27A, FBP1 (Fructose- 1,6-bisphosphatase 1) and ACAD9 (Acyl-CoA dehydrogenase family member 9). Variants in RAB27A lead to Griscelli syndrome type 2, hypopigmentation and HLH predisposition. Discussion: Lymphoma is frequently seen in patients with hypomorphic mutations of genes predisposing to HLH. We hypothesize that the variants in FBP1 and ACAD9 might aggravate the clinical and immune phenotype, influence serial killing and lytic granule polarization by CD8 T cells. Understanding of the interplay between the multiple variants identified by whole exome sequencing (WES) is essential for correct interpretation of the immune phenotype and important for critical treatment decisions. [ABSTRACT FROM AUTHOR]

Published
2023
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47. Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency

Author

Blanco, Elena, Camps, Carme, Bahal, Sameer, Kerai, Mohit D., Ferla, Matteo P., Rochussen, Adam M., Handel, Adam E., Golwala, Zainab M., Spiridou Goncalves, Helena, Kricke, Susanne, Klein, Fabian, Zhang, Fang, Zinghirino, Federica, Evans, Grace, Keane, Thomas M., Lizot, Sabrina, Kusters, Maaike A.A., Iro, Mildred A., Patel, Sanjay V., Morris, Emma C., Burns, Siobhan O., Radcliffe, Ruth, Vasudevan, Pradeep, Price, Arthur, Gillham, Olivia, Valdebenito, Gabriel E., Stewart, Grant S., Worth, Austen, Adams, Stuart P., Duchen, Michael, André, Isabelle, Adams, David J., Santili, Giorgia, Gilmour, Kimberly C., Holländer, Georg A., Davies, E. Graham, Taylor, Jenny C., Griffiths, Gillian M., Thrasher, Adrian J., Dhalla, Fatima, and Kreins, Alexandra Y.

Abstract

The importance of calcium (Ca2+) as a second messenger in T cell signaling is exemplified by genetic deficiencies of STIM1 and ORAI1, which abolish store-operated Ca2+ entry (SOCE) resulting in combined immunodeficiency (CID). We report five unrelated patients with de novo missense variants in ITPR3, encoding a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca2+ channel in the endoplasmic reticulum (ER) membrane responsible for the release of ER Ca2+ required to trigger SOCE, and for Ca2+ transfer to other organelles. The patients presented with CID, abnormal T cell Ca2+ homeostasis, incompletely penetrant ectodermal dysplasia, and multisystem disease. Their predominant T cell immunodeficiency is characterized by significant T cell lymphopenia, defects in late stages of thymic T cell development, and impaired function of peripheral T cells, including inadequate NF-κB- and NFAT-mediated, proliferative, and metabolic responses to activation. Pathogenicity is not due to haploinsufficiency, rather ITPR3 protein variants interfere with IP3R channel function leading to depletion of ER Ca2+ stores and blunted SOCE in T cells.

Published
2025
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