Signal transduction in lymphocytes
Lead Research Organisation:
MRC National Inst for Medical Research
Abstract
Lymphocytes are white blood cells which fight infections such as viruses and bacteria. When a lymphocyte encounters such a pathogen it reacts by changing from a resting state where the cells does little more than circulate around the body, to an activated state where it divides rapidly, makes antibodies, enters infected tissues and kills infected cells. This transformation requires signals to travel from the surface of the lymphocyte all the way to its nucleus, where the transformation process is controlled. The aim of this project is to understand the various biochemical reactions which produce this signal.
Technical Summary
General Aims Relevance Health Issues The main objectives of this project are to understand how signals are transduced from the antigen receptors of lymphocytes. In particular we have used ES cell technology to generate mouse strains with deficiencies in specific signal transducing proteins. The effect of the mutations has then been analysed on lymphocyte development, activation and function. The work is relevant to human health problems involving immune responses, e.g. autoimmunity, immunodeficiency, transplantation. Precise Scientific Objectives The precise scientific objectives have been to investigate the role of a number of specific signalling proteins: Syk, ZAP-70, Vav, CD45, Rac1 and Rac2 in transducing signals from antigen receptors of B and T lymphocytes, analysed in the context of lymphocyte development, function and signalling biochemistry. Plan of Investigation We have generated mice carrying mutations in Syk, CD45, Vav and Rac1. We have imported mice with mutations in a number of other signalling molecules and analysed lymphocytes development, function and signalling in mice carrying singly double or even triple mutations. Subsequent Scientific/Medical Opportunities We hope the work will give rise to a better understanding of the way in which antigen receptors transduce signals into lymphocytes, using primary non-transformed cells.
Organisations
- MRC National Inst for Medical Research, United Kingdom (Lead Research Organisation)
- University College London, United Kingdom (Collaboration)
- Imperial College London, United Kingdom (Collaboration)
- Ludwig Maximilians University Munich (Collaboration)
- Cancer Research UK Cambridge Institute (Collaboration)
- University of Cape Town (Collaboration)
- Columbia University, United States (Collaboration)
- Medical Research Council (Collaboration)
- University of Birmingham, United Kingdom (Collaboration)
- Technical University of Munich (Collaboration)
- Ludwig Institute for Cancer Research (Collaboration)
- National Institutes of Health, United States (Collaboration)
- Imperial Cancer Research Fund (Collaboration)
- Queen Mary, University of London, United Kingdom (Collaboration)
- Washington University in St Louis, United States (Collaboration)
- University of Pennsylvania, United States (Collaboration)
- Massachusetts Institute of Technology (Collaboration)
- Erasmus MC (Collaboration)
- San Raffaele Hospital (Collaboration)
- University of Tokyo (Collaboration)
People |
ORCID iD |
| Victor Leszek Tybulewicz (Principal Investigator) |
Publications
Ackermann JA
(2015)
Syk tyrosine kinase is critical for B cell antibody responses and memory B cell survival.
in Journal of immunology (Baltimore, Md. : 1950)
Ahmed MM
(2013)
Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain.
in Human molecular genetics
Alford KA
(2010)
Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome.
in Blood
Atif SM
(2015)
Rapid CD4+ T-cell responses to bacterial flagellin require dendritic cell expression of Syk and CARD9.
in European journal of immunology
Brazão TF
(2016)
Long noncoding RNAs in B-cell development and activation.
in Blood
Canzonetta C
(2008)
DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.
in American journal of human genetics
Cleary JO
(2011)
Structural correlates of active-staining following magnetic resonance microscopy in the mouse brain.
in NeuroImage
Corbetta S
(2009)
Essential role of Rac1 and Rac3 GTPases in neuronal development.
in FASEB journal : official publication of the Federation of American Societies for Experimental Biology
D'Amico G
(2010)
Endothelial-Rac1 is not required for tumor angiogenesis unless alphavbeta3-integrin is absent.
in PloS one
D'Amico G
(2009)
Regulation of lymphatic-blood vessel separation by endothelial Rac1.
in Development (Cambridge, England)
Dennehy KM
(2008)
Syk kinase is required for collaborative cytokine production induced through Dectin-1 and Toll-like receptors.
in European journal of immunology
Depoil D
(2008)
CD19 is essential for B cell activation by promoting B cell receptor-antigen microcluster formation in response to membrane-bound ligand.
in Nature immunology
Devoy A
(2011)
Genomically humanized mice: technologies and promises.
in Nature reviews. Genetics
Duchon A
(2011)
The telomeric part of the human chromosome 21 from Cstb to Prmt2 is not necessary for the locomotor and short-term memory deficits observed in the Tc1 mouse model of Down syndrome.
in Behavioural brain research
Dumont C
(2008)
Characterization of the roles of Rac1 and Rac2 GTPases in lymphocyte development.
in Methods in enzymology
Dumont C
(2009)
Rac GTPases play critical roles in early T-cell development.
in Blood
Dunlevy L
(2010)
Down's syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse.
in Cardiovascular research
Fallah-Arani F
(2008)
Redundant role for Zap70 in B cell development and activation.
in European journal of immunology
Faroudi M
(2010)
Critical roles for Rac GTPases in T-cell migration to and within lymph nodes.
in Blood
Finney BA
(2012)
CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development.
in Blood
Fisher EM
(2009)
New approaches for modelling sporadic genetic disease in the mouse.
in Disease models & mechanisms
Galante M
(2009)
Impairments in motor coordination without major changes in cerebellar plasticity in the Tc1 mouse model of Down syndrome.
in Human molecular genetics
Grizenkova J
(2012)
Overexpression of the Hspa13 (Stch) gene reduces prion disease incubation time in mice.
in Proceedings of the National Academy of Sciences of the United States of America
Gross O
(2009)
Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.
in Nature
Hartweger H
(2014)
Themis2 is not required for B cell development, activation, and antibody responses.
in Journal of immunology (Baltimore, Md. : 1950)
Haubert D
(2012)
Vav1 GEF activity is required for T cell mediated allograft rejection.
in Transplant immunology
Henderson RB
(2010)
A novel Rac-dependent checkpoint in B cell development controls entry into the splenic white pulp and cell survival.
in The Journal of experimental medicine
Hughan SC
(2007)
GPVI potentiation of platelet activation by thrombin and adhesion molecules independent of Src kinases and Syk.
in Arteriosclerosis, thrombosis, and vascular biology
Izawa K
(2007)
Functional analysis of activating receptor LMIR4 as a counterpart of inhibitory receptor LMIR3.
in The Journal of biological chemistry
Jacque E
(2014)
IKK-induced NF-?B1 p105 proteolysis is critical for B cell antibody responses to T cell-dependent antigen.
in The Journal of experimental medicine
Jacque E
(2015)
BAFF activation of the ERK5 MAP kinase pathway regulates B cell survival.
in The Journal of experimental medicine
Kissil JL
(2007)
Requirement for Rac1 in a K-ras induced lung cancer in the mouse.
in Cancer research
Ksionda O
(2012)
Mechanism and function of Vav1 localisation in TCR signalling.
in Journal of cell science
Köchl R
(2016)
WNK1 kinase balances T cell adhesion versus migration in vivo.
in Nature immunology
Lana-Elola E
(2016)
Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel.
in eLife
Lana-Elola E
(2011)
Down syndrome: searching for the genetic culprits.
in Disease models & mechanisms
LeibundGut-Landmann S
(2007)
Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17.
in Nature immunology
Liang B
(2008)
Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II.
in Journal of immunology (Baltimore, Md. : 1950)
Ma D
(2014)
Automatic structural parcellation of mouse brain MRI using multi-atlas label fusion.
in PloS one
Mensah A
(2007)
An additional human chromosome 21 causes suppression of neural fate of pluripotent mouse embryonic stem cells in a teratoma model.
in BMC developmental biology
Morice E
(2008)
Preservation of long-term memory and synaptic plasticity despite short-term impairments in the Tc1 mouse model of Down syndrome.
in Learning & memory (Cold Spring Harbor, N.Y.)
Mócsai A
(2010)
The SYK tyrosine kinase: a crucial player in diverse biological functions.
in Nature reviews. Immunology
Nodari A
(2007)
Beta1 integrin activates Rac1 in Schwann cells to generate radial lamellae during axonal sorting and myelination.
in The Journal of cell biology
| Description | EMBO Fellowship-2006 |
| Amount | £330 (GBP) |
| Organisation | European Molecular Biology Organisation |
| Sector | Charity/Non Profit |
| Country | Germany |
| Start | 02/2006 |
| End | 04/2007 |
| Description | EU-Integrated Project-FP6 |
| Amount | € 430,068 (EUR) |
| Funding ID | LSHG-CT-2006-037627 |
| Organisation | Sixth Framework Programme (FP6) |
| Sector | Public |
| Country | European Union (EU) |
| Start | 12/2006 |
| End | 11/2010 |
| Description | EU-Marie Curie Intra-European Fellowship-2007 |
| Amount | € 158,479 (EUR) |
| Funding ID | MEIF-CT-2006-025449 |
| Organisation | Marie Sklodowska-Curie Actions |
| Sector | Charity/Non Profit |
| Country | Global |
| Start | 05/2007 |
| End | 04/2009 |
| Description | Leukaemia Research Project Grant 2006 |
| Amount | £195,725 (GBP) |
| Organisation | Leukaemia and Lymphoma Research |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 07/2006 |
| End | 07/2009 |
| Description | Leukaemia Research Project Grant 2006 |
| Amount | £176,390 (GBP) |
| Organisation | Leukaemia and Lymphoma Research |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2006 |
| End | 12/2008 |
| Description | MRC Research Grant |
| Amount | £31,867 (GBP) |
| Funding ID | G0801110 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2009 |
| End | 04/2014 |
| Description | Senior Investigator Award |
| Amount | £1,741,765 (GBP) |
| Funding ID | 098328 |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2014 |
| End | 12/2020 |
| Description | Strategic Award |
| Amount | £675,134 (GBP) |
| Funding ID | 098330 |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 12/2012 |
| End | 11/2017 |
| Description | Wellcome Trust Research Grant |
| Amount | £424,573 (GBP) |
| Funding ID | 089185 |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2010 |
| End | 01/2014 |
| Description | Wellcome Trust Research Grant |
| Amount | £1,059,590 (GBP) |
| Funding ID | 080174 |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 03/2007 |
| End | 02/2014 |
| Title | Mouse with conditional allele of Rac1 |
| Description | Mouse with conditional allele of Rac1. |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Provided To Others? | Yes |
| Impact | Mouse strain allows study of role of Rac1 in adult tissues, overcoming lethality of constitutive mutation |
| URL | http://www.ncbi.nlm.nih.gov/pubmed/14564011 |
| Title | SYK mice |
| Description | Mice heterozygous for a disrupted Syk gene (Syk+/-) |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Provided To Others? | Yes |
| Impact | Also licenced to pharmaceutical company |
| URL | http://www.ncbi.nlm.nih.gov/pubmed/7477352 |
| Title | Tc1 mice |
| Description | Mouse model of Down syndrome |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Provided To Others? | Yes |
| Impact | Allow study of Down syndrome |
| URL | http://www.ncbi.nlm.nih.gov/pubmed/16179473 |
| Title | Vav-1 KO mice |
| Description | Mouse model |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Provided To Others? | Yes |
| Impact | Also licensed to Pharmaceutical company |
| URL | http://www.ncbi.nlm.nih.gov/pubmed/7700358 |
| Description | ß1 integrins activate Rac1 in Schwann cells to generate radial lamellae during axonal sorting |
| Organisation | San Raffaele Hospital |
| Department | San Raffaele Scientific Institute (SRSI) |
| Country | Italy |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 17576799 |
| Description | An unexpected role for IL-3 in the embryonic development of hematopoietic stem cells |
| Organisation | Erasmus MC |
| Country | Netherlands |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 16890157 |
| Description | Analysis of mouse LMIR5/CLM7 as an activating receptor: differential regulation of LMIR5/CLM7 in mouse versus human cells |
| Organisation | University of Tokyo |
| Country | Japan |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 17928527 |
| Description | Angiogenesis and Lymphangiogenesis |
| Organisation | Queen Mary University of London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 19906871 PMID: 20339539 PMID: 20535211 |
| Description | B cell signaling |
| Organisation | Cancer Research UK |
| Department | Cancer Research UK London Research Institute (LRI) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publications |
| Impact | PMID: 18059271 PMID: 18191593 |
| Description | Brain function in mouse model of Down Syndrome |
| Organisation | Medical Research Council (MRC) |
| Department | MRC National Institute for Medical Research (NIMR) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publications |
| Impact | PMID: 18626093 PMID: 19181682 |
| Description | Co-stimulation of Toll-like receptor-mediated innate immune responses by the Syk kinase pathway |
| Organisation | University of Cape Town |
| Country | South Africa |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 18200499 |
| Description | Critical structural role for the PH and C1 domains of the Vav1 exchange factor |
| Organisation | Medical Research Council (MRC) |
| Department | MRC National Institute for Medical Research (NIMR) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Experiments and analysis |
| Collaborator Contribution | Publication |
| Impact | PMID: 18511940 |
| Description | Dendritic cell signaling |
| Organisation | Cancer Research UK |
| Department | Cancer Research UK London Research Institute (LRI) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publications |
| Impact | PMID: 17458858 PMID: 17450144 PMID: 19703985 |
| Description | Down Syndrome |
| Organisation | University College London |
| Department | Institute of Neurology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Joint grant applications, joint research program, joint publications |
| Collaborator Contribution | Joint grant applications, joint research program, joint publications |
| Impact | PMID: 16987872; PMID: 18047653; PMID: 18626093; PMID: 18771760; PMID: 18787134; PMID: 19001410; PMID: 19181682; PMID: 19726804; PMID: 20154221; PMID: 20535211; PMID: 20697343. |
| Description | Essential role of Rac1 and Rac3 GTPases neuronal development |
| Organisation | San Raffaele Hospital |
| Department | San Raffaele Scientific Institute (SRSI) |
| Country | Italy |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 19126596 |
| Description | Functional analysis of activating receptor LMIR4 as a counterpart of inhibitory receptor LMIR3 |
| Organisation | University of Tokyo |
| Country | Japan |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 17438331 |
| Description | Heart development in Down Syndrome |
| Organisation | Medical Research Council (MRC) |
| Department | MRC National Institute for Medical Research (NIMR) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Mice, joint research planning |
| Collaborator Contribution | Joint publication. PMID: 20558441 |
| Impact | PMID: 20558441 |
| Description | Nf-kB and ERK signaling |
| Organisation | Medical Research Council (MRC) |
| Department | MRC National Institute for Medical Research (NIMR) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Advice |
| Collaborator Contribution | Publication |
| Impact | PMID: 16633345 PMID: 19060899 |
| Description | Platelet signaling |
| Organisation | University of Birmingham |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 16174766 PMID: 17110603 |
| Description | Rac GTPases sensitize T cells to Fas-mediated apoptosis through regulation of cytoskeletal remodelling |
| Organisation | National Institutes of Health (NIH) |
| Country | United States |
| Sector | Public |
| PI Contribution | Studies of activation induced T cell death |
| Collaborator Contribution | Publication |
| Impact | PMID: 17982024 |
| Description | Rac1 and Rac2 regulate cell morphology but are not essential for migration |
| Organisation | Ludwig Institute for Cancer Research |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 16772332 |
| Description | Regulatory T Cells Inhibit Dendritic Cells by LAG-3 Engagement of MHC Class II |
| Organisation | Columbia University |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 18424711 |
| Description | Requirement for Rac1 in a K-ras induced lung cancer in the mouse |
| Organisation | Massachusetts Institute of Technology |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 17804720 |
| Description | Studies of Down Syndrome mouse models |
| Organisation | Queen Mary University of London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publications |
| Impact | PMID: 18047653 PMID: 18771760 PMID: 19001410 PMID: 20697343 |
| Description | Syk and Slp-76 mutant mice reveal a cell-autonomous hematopoietic cell contribution to vascular development |
| Organisation | University of Pennsylvania |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 16950126 |
| Description | Syk kinase signaling couples to the Nalp3 inflammasome for anti-fungal host defense |
| Organisation | Technical University of Munich |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 19339971 |
| Start Year | 2008 |
| Description | Syk, c-Src, the avß3 integrin and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption |
| Organisation | Washington University in St Louis |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 17353363 |
| Description | Syk-mediated translocation of PI3Kd to the leading edge controls lamellipodium formation and migration of leukocytes |
| Organisation | Ludwig Maximilian University of Munich (LMU Munich) |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 17987119 |
| Description | Tissue-specific transcription is directed by genome sequence in an aneuploid mouse strain carrying human chromosome 21 |
| Organisation | Cancer Research UK Cambridge Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Mice |
| Collaborator Contribution | Publication |
| Impact | PMID: 18787134 |
| Description | Vav1 activity is required for primed T cell retention in non-lymphoid antigenic tissue |
| Organisation | Imperial College London |
| Department | Division of Immunology and Inflammation |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Mice and advice |
| Collaborator Contribution | Publication |
| Impact | PMID: 19060239 |