The role of death receptor 3 in peripheral CD8+ T cell function

Lead Research Organisation: University of Wales
Department Name: UNLISTED

Abstract

Death Receptor 3 (DR3) is a member of the tumour necrosis factor receptor superfamily of proteins that are involved in regulation and development of the immune response. However, the specific biological function of DR3 has remained obscure. Our preliminary research has identified a role for DR3 in the development and function of CD8+ T cells. CD8+ T cells represent one of the cytotoxic arms of the immune response, generating cells that kill virus-infected and cancerous targets. CD8+ T cells can also be responsible for autoimmunity when their regulation is disrupted. This project is designed to define the role played by DR3 in CD8+ T cell function. In so doing, we may learn how to manipulate the CD8+ T cell response, which is a major target for immunotherapies against virus infections, cancers and autoimmune disease.

Technical Summary

Of the death-domain containing tumour necrosis factor receptor (TNFR) superfamily members, death receptor 3 (DR3) is the closest relative to TNFR1. Like TNFR1, the in vitro over-expression of DR3 can lead to either cell death or cell survival/activation. However, little is known of the in vivo role of DR3. Previously, I have generated mice deficient for the DR3 gene (DR3ko), which showed a defect in the removal of self-reactive CD8+ thymocytes. Recently, I have identified more phenotypic differences in peripheral DR3koCD8+ T cells, including: (i) decreased CD8+ proliferation following stimulation with certain, polyclonal T cell activators; (ii) decreases in the proportion of CD8+ T cells expressing memory markers. CD8+ T cells represent the cytotoxic arm of the adaptive immune response, killing target cells in a MHC I-restricted manner. Impairment of CD8+ T cell regulation through loss of DR3 may lead to dysfunctional CD8+ T cells and disrupted immunity to infections and cancer or altered susceptibility to autoimmunity. This proposal is designed to characterise the defects in DR3koCD8+ T cells and investigate whether they result in CD8+ immune dysfunction in vivo. Specifically, there are 5 major experimental aims:
AIM I. To characterise the in vitro proliferative defect in murine DR3koCD8+ T cells
AIM II. To investigate the in vivo role of DR3 in CD8+ T cell proliferation and homeostasis
AIM III. To investigate the in vivo role of DR3 in CD8+ T cell-dependent anti-viral immunity
AIM IV. To investigate the in vivo role of DR3 in the generation of self-reactive CD8+ T cells
AIM V. To define the role of DR3 in CD8+ T cell function in man

Publications

10 25 50
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Al-Lamki RS (2008) TL1A both promotes and protects from renal inflammation and injury. in Journal of the American Society of Nephrology : JASN

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Calder CJ (2012) An essential role for death receptor 3 in experimental autoimmune uveoretinitis. in Ocular immunology and inflammation

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Chong LK (2008) Proliferation and interleukin 5 production by CD8hi CD57+ T cells. in European journal of immunology

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Jones GW (2011) Naive and activated T cells display differential responsiveness to TL1A that affects Th17 generation, maintenance, and proliferation. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

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McLaren JE (2010) The TNF-like protein 1A-death receptor 3 pathway promotes macrophage foam cell formation in vitro. in Journal of immunology (Baltimore, Md. : 1950)

 
Description ARC PhD Studentship
Amount £80,530 (GBP)
Organisation Versus Arthritis 
Start 10/2009 
End 09/2012
 
Description BBSRC CASE Studentship (GSK)
Amount £97,110 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2009 
End 09/2013
 
Description MRC Collaboration Grant
Amount £188,888 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2006 
End 03/2009
 
Description MRC Project Grant
Amount £534,818 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 12/2009 
End 05/2013
 
Description PhD Studentship
Amount £53,000 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description Arthritis 
Organisation Cardiff University
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Staff, intellectual input and funding for expts
Collaborator Contribution Joint publication
Impact Publications - PMID: 18824582 Grants - ARC PhD studentship awarded in 2009
 
Description Asthma 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Staff, reagents and intellectual input
Collaborator Contribution Intellectual input
Impact Successful grant funding - BBSRC/GSK CASE Studentship awarded in 2009
 
Description EAE 
Organisation National Institutes of Health (NIH)
Country United States 
Sector Public 
PI Contribution Reagents and intellectual input
Collaborator Contribution Publication
Impact Publications - PMID: 18571443
 
Description Lung 
Organisation University Hospital of Wales
Department Department of Medical Biochemistry and Immunology
Country United Kingdom 
Sector Hospitals 
PI Contribution Reagents and intellectual input
Collaborator Contribution Intellectual input
Impact Successful grant funding - BBSRC/GSK CASE Studentship awarded in 2009
Start Year 2008
 
Description MCMV 
Organisation University Hospital of Wales
Department Department of Medical Biochemistry and Immunology
Country United Kingdom 
Sector Hospitals 
PI Contribution Staff, reagents, intellectual input
Collaborator Contribution Intellectual input and reagents
Impact Successful grant funding - MRC Project Grant awarded in 2009
Start Year 2007
 
Description Neurology 
Organisation University of Cambridge
Department Department of Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution Reagents and intellectual input
Collaborator Contribution Publication
Impact Publication - PMID: 18287561
 
Description Poster at MRC Showcase 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Poster at the MRC Immunotherapies and Vaccines Showcase at the Sanger Institute, Cambridge

Runner-up Industry Poster Award and some interest from Pharma, though no funding as yet
Year(s) Of Engagement Activity 2008