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.

Publications

10 25 50
 
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 £176,390 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2006 
End 12/2008
 
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 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