Gillian Griffiths

Last updated

Gillian Griffiths
Born
Gillian Margaret Griffiths
Alma mater
Awards
Scientific career
Fields
Institutions
Thesis Molecular analysis of the immune response  (1983)
Doctoral advisor César Milstein
Website med.cam.ac.uk/griffiths

Gillian Margaret Griffiths is a British cell biologist and immunologist. Griffiths was one of the first to show that immune cells have specialised mechanisms of secretion, and identified proteins and mechanisms that control cytotoxic T lymphocyte secretion. [1] [2] [3] [4] [5] [6]

Contents

Current research

Griffiths is Professor of Cell Biology and Immunology at the University of Cambridge, running a research laboratory at the Cambridge Institute for Medical Research. She was Director of CIMR from 2013 until 2017. In 2024, she was appointed as the new Chair of the Department of Cell Biology at Yale School of Medicine, effective 1st April 2025. [7] Her work leverages advanced microscopy techniques to image cytotoxic T lymphocytes (CTLs) as they kill cancerous target cells, as well as functional assays and biochemical techniques. [8] Recently, work from her lab has uncovered a link between mitochondrial protein translation and CTL cytotoxicity, [9] termination of T cell receptor signalling at the immune synapse via ectocytosis (outward membrane budding), [10] and a link between transcription of new RNAs and the ability of CTLs to infiltrate target cell clumps. [11]

Education

When she was young, Griffiths initially thought she might like to be an ecologist. However, she began her scientific career at University College London by studying immunology. She continued in the subject, undertaking her PhD at the MRC Laboratory of Molecular Biology in Cambridge supervised by César Milstein. [12]

Awards and honours

Griffiths' research is largely funded by the Wellcome Trust, having been awarded Principle Research Fellowships in 2014 and 2019, and a Discovery Award in 2024. [13] [14] [15] She is a Fellow at King's College, Cambridge and was elected a Fellow of the Royal Society in 2013. Her nomination for the Royal Society reads

Gillian Griffiths has made key contributions to the fields of both cell biology and immunology, introducing important new concepts into both fields. Gillian Griffiths was one of the first to show that immune cells use specialised mechanisms of secretion, identifying the proteins and mechanisms controlling secretion from cytotoxic T lymphocytes via high resolution live cell microscopy, biochemical approaches, and by studying human genetic diseases. Her work has identified a new and unexpected role for the centrosome in exocytosis, and revealed that centrosome docking at the plasma membrane provides a focal point for exocytosis. Her work is both elegant and insightful. [1]

Related Research Articles

<span class="mw-page-title-main">Immune system</span> Biological system protecting an organism against disease

The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as cancer cells, parasitic worms, and also objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens such as viruses or bacteria, or cells that are damaged in other ways.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on major histocompatibility complex I (MHC-I) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

<span class="mw-page-title-main">Perforin-1</span> Mammalian protein found in Homo sapiens

Perforin-1 Perforin (PRF), encoded by the PRF1 gene, is a pore-forming toxic protein housed in the secretory granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Together, these cells are known as cytotoxic lymphocytes (CLs).

Granzymes are serine proteases released by cytoplasmic granules within cytotoxic T cells and natural killer (NK) cells. They induce programmed cell death (apoptosis) in the target cell, thus eliminating cells that have become cancerous or are infected with viruses or bacteria. Granzymes also kill bacteria and inhibit viral replication. In NK cells and T cells, granzymes are packaged in cytotoxic granules along with perforin. Granzymes can also be detected in the rough endoplasmic reticulum, golgi complex, and the trans-golgi reticulum. The contents of the cytotoxic granules function to permit entry of the granzymes into the target cell cytosol. The granules are released into an immune synapse formed with a target cell, where perforin mediates the delivery of the granzymes into endosomes in the target cell, and finally into the target cell cytosol. Granzymes are part of the serine esterase family. They are closely related to other immune serine proteases expressed by innate immune cells, such as neutrophil elastase and cathepsin G.

<span class="mw-page-title-main">Adaptive immune system</span> Subsystem of the immune system

The adaptive immune system, AIS, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized cells, organs, and processes that eliminate pathogens specifically. The acquired immune system is one of the two main immunity strategies found in vertebrates.

<span class="mw-page-title-main">Immunological synapse</span> Interface between lymphocyte and target cell

In immunology, an immunological synapse is the interface between an antigen-presenting cell or target cell and a lymphocyte such as a T cell, B cell, or natural killer cell. The interface was originally named after the neuronal synapse, with which it shares the main structural pattern. An immunological synapse consists of molecules involved in T cell activation, which compose typical patterns—activation clusters. Immunological synapses are the subject of much ongoing research.

<span class="mw-page-title-main">Antigen presentation</span> Vital immune process that is essential for T cell immune response triggering

Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment can be recognized by a T-cell receptor. Specifically, the fragment, bound to the major histocompatibility complex (MHC), is transported to the surface of the antigen-presenting cell, a process known as presentation. If there has been an infection with viruses or bacteria, the antigen-presenting cell will present an endogenous or exogenous peptide fragment derived from the antigen by MHC molecules. There are two types of MHC molecules which differ in the behaviour of the antigens: MHC class I molecules (MHC-I) bind peptides from the cell cytosol, while peptides generated in the endocytic vesicles after internalisation are bound to MHC class II (MHC-II). Cellular membranes separate these two cellular environments - intracellular and extracellular. Each T cell can only recognize tens to hundreds of copies of a unique sequence of a single peptide among thousands of other peptides presented on the same cell, because an MHC molecule in one cell can bind to quite a large range of peptides. Predicting which antigens will be presented to the immune system by a certain MHC/HLA type is difficult, but the technology involved is improving.

<span class="mw-page-title-main">Carboxyfluorescein succinimidyl ester</span> Chemical compound

Carboxyfluorescein succinimidyl ester (CFSE) is a fluorescent cell staining dye. CFSE is cell permeable and covalently couples, via its succinimidyl group, to intracellular molecules, notably, to intracellular lysine residues and other amine sources. Due to this covalent coupling reaction, fluorescent CFSE can be retained within cells for extremely long periods. Also, due to this stable linkage, once incorporated within cells, the dye is not transferred to adjacent cells.

<span class="mw-page-title-main">TIA1</span> Mammalian protein found in Homo sapiens

TIA1 or Tia1 cytotoxic granule-associated rna binding protein is a 3'UTR mRNA binding protein that can bind the 5'TOP sequence of 5'TOP mRNAs. It is associated with programmed cell death (apoptosis) and regulates alternative splicing of the gene encoding the Fas receptor, an apoptosis-promoting protein. Under stress conditions, TIA1 localizes to cellular RNA-protein conglomerations called stress granules. It is encoded by the TIA1 gene.

<span class="mw-page-title-main">Cancer immunology</span> Study of the role of the immune system in cancer

Cancer immunology (immuno-oncology) is an interdisciplinary branch of biology and a sub-discipline of immunology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.

<span class="mw-page-title-main">ICAM2</span> Protein-coding gene in the species Homo sapiens

Intercellular adhesion molecule 2 (ICAM2), also known as CD102, is a human gene, and the protein resulting from it.

<span class="mw-page-title-main">NCR3</span> Mammalian protein found in Homo sapiens

Natural cytotoxicity triggering receptor 3 is a protein that in humans is encoded by the NCR3 gene. NCR3 has also been designated as CD337 and as NKp30. NCR3 belongs to the family of NCR membrane receptors together with NCR1 (NKp46) and NCR2 (NKp44).

<span class="mw-page-title-main">CD226</span> Protein found in humans

CD226, PTA1 or DNAM-1 is a ~65 kDa immunoglobulin-like transmembrane glycoprotein expressed on the surface of natural killer cells, NK T cell, B cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes and T cells.

<span class="mw-page-title-main">GZMK</span> Protein-coding gene in the species Homo sapiens

Granzyme K (GrK) is a protein that is encoded by the GZMK gene on chromosome 5 in humans. Granzymes are a family of serine proteases which have various intracellular and extracellular roles. GrK is found in granules of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), and is traditionally described as being cytotoxic towards targeted foreign, infected, or cancerous cells. NK cells and CTLs can induce apoptosis through the granule secretory pathway, which involves the secretion of granzymes along with perforin at immunological synapses.

Priming is the first contact that antigen-specific T helper cell precursors have with an antigen. It is essential to the T helper cells' subsequent interaction with B cells to produce antibodies. Priming of antigen-specific naive lymphocytes occurs when antigen is presented to them in immunogenic form. Subsequently, the primed cells will differentiate either into effector cells or into memory cells that can mount stronger and faster response to second and upcoming immune challenges. T and B cell priming occurs in the secondary lymphoid organs.

<span class="mw-page-title-main">Trogocytosis</span>

Trogocytosis is when a cell nibbles another cell. It is a process whereby lymphocytes conjugated to antigen-presenting cells extract surface molecules from these cells and express them on their own surface. The molecular reorganization occurring at the interface between the lymphocyte and the antigen-presenting cell during conjugation is also called "immunological synapse".

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3 regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25FOXP3LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

Kiss-and-run fusion is a type of synaptic vesicle release where the vesicle opens and closes transiently. In this form of exocytosis, the vesicle docks and transiently fuses at the presynaptic membrane and releases its neurotransmitters across the synapse, after which the vesicle can then be reused.

Daniel Michael Davis is Head of Life Sciences and Professor of Immunology at Imperial College London. Davis was previously Professor of Immunology at the University of Manchester. He is the author of The Secret Body, The Beautiful Cure and The Compatibility Gene. His research, using microscopy to study immune cell biology has helped understand how immune cells interact with each other.

References

  1. 1 2 "Professor Gillian Griffiths FMedSci FRS". The Royal Society. Archived from the original on 20 June 2019. Retrieved 11 October 2013.
  2. Stinchcombe, J. C.; Salio, M; Cerundolo, V; Pende, D; Arico, M; Griffiths, G. M. (2011). "Centriole polarisation to the immunological synapse directs secretion from cytolytic cells of both the innate and adaptive immune systems". BMC Biology. 9: 45. doi: 10.1186/1741-7007-9-45 . PMC   3149597 . PMID   21711522.
  3. Tsun, A; Qureshi, I; Stinchcombe, J. C.; Jenkins, M. R.; de la Roche, M; Kleczkowska, J; Zamoyska, R; Griffiths, G. M. (2011). "Centrosome docking at the immunological synapse is controlled by Lck signaling". The Journal of Cell Biology. 192 (4): 663–74. doi:10.1083/jcb.201008140. PMC   3044125 . PMID   21339332.
  4. Griffiths, G. M.; Tsun, A.; Stinchcombe, J. C. (2010). "The immunological synapse: A focal point for endocytosis and exocytosis". The Journal of Cell Biology. 189 (3): 399–406. doi:10.1083/jcb.201002027. PMC   2867296 . PMID   20439993.
  5. Cetica, V; Santoro, A; Gilmour, K. C.; Sieni, E; Beutel, K; Pende, D; Marcenaro, S; Koch, F; Grieve, S; Wheeler, R; Zhao, F; Zur Stadt, U; Griffiths, G. M.; Aricò, M (2010). "STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5". Journal of Medical Genetics. 47 (9): 595–600. doi:10.1136/jmg.2009.075341. PMC   4115259 . PMID   20798128.
  6. Gillian Griffiths's publications indexed by the Scopus bibliographic database. (subscription required)
  7. "Gillian Griffiths Named Chair of the Department of Cell Biology". 16 October 2024. Retrieved 3 January 2025.
  8. "Griffiths Lab Website".
  9. Miriam Lisci; Philippa R. Barton; Lyra O. Randzavola; Claire Y. Ma; Julia M. Marchingo; Doreen A. Cantrell; Vincent Paupe; Julien Prudent; Jane C. Stinchcombe; Gillian M. Griffiths (15 October 2021). "Mitochondrial translation is required for sustained killing by cytotoxic T cells". Science. 374 (6565). doi:10.1126/science.abe9977.
  10. Jane C. Stinchcombe; Yukako Asano; Christopher J. G. Kaufman; Kristin Böhlig; Christopher J. Peddie; Lucy M Collinson; André Nadler; Gillian M. Griffiths (25 May 2023). "Ectocytosis renders T cell receptor signaling self-limiting at the immune synapse". Science. 380 (6647): 818–823. Bibcode:2023Sci...380..818S. doi:10.1126/science.abp8933. PMC   7614748 . PMID   37228189.
  11. Arianne C. Richard; Claire Y. Ma; John C. Marioni; Gillian M. Griffiths (20 October 2023). "Cytotoxic T lymphocytes require transcription for infiltration but not target cell lysis". EMBO Reports. 24 (11): e57653. doi:10.15252/embr.202357653. PMC   10626425 . PMID   37860838.
  12. Sedwick, C. (2013). "Gillian Griffiths: How T cells get on target". The Journal of Cell Biology. 200 (1): 4–5. doi:10.1083/jcb.2001pi. PMC   3542799 . PMID   23295346.
  13. "Molecular mechanisms controlling polarised secretion at the immunological synapse".
  14. "Molecular mechanisms controlling cytotoxic T lymphocyte (CTL) killing: From genes to secretion".
  15. "Dynamic changes at the immune synapse controlling CTL function - Grants Awarded".
  16. "Buchanan Medallist 2019". Royal Society. Retrieved 5 October 2019.