Natural cellular cytotoxicity in tumour surveillance and immunity to infections

Lead Research Organisation: Babraham Institute
Department Name: Lymphocyte Signalling and Development

Abstract

We try to find out how white blood cells called natural killer (NK) cells fight microbes and tumours.
We know that NK cells have a natural tendency to kill infected and tumour cells in the test tube, however it is difficult to study these mechanisms in the human body. So we use mice in our research, because their immune defences are well defined and fairly similar to ours.
By modelling human diseases in laboratory mice, we are gaining important insights into how to harness the potential of our natural resources to fight infections and cancer.
For example, we have identified a single gene that regulates the killer cell’s action and protects against viral infections and blood-born cancer. We are now trying to discover how NK cells attack a type of skin cancer known as melanoma.
By learning more about how our natural defences work, we will be able to think of more effective cures against infection and cancer.

Technical Summary

We propose a new and unique mouse model of NK cell-selective deficient cytotoxicity. This model is based on the first Natural Killer (NK)-specific knock-out mouse, which expresses an inactive form of phospholipase C-gamma2. PLCg2 is a key regulator of natural cytotoxicity but not acquired cytotoxicity. Thus, NK cells will be faulty whereas cytotoxic T lymphocytes (CTL) responses will be intact. By challenging these mice with mouse cytomegalovirus and Listeria monocytogenes, we will be able to address the question of how innate immunity shapes the outcome of adaptive T cell responses to infectious pathogens. We will also be able to uncouple NK and CTL cytotoxicity in the contraction phase of lymphocyte responses. By crossing this mouse with a mouse model of spontaneous melanoma we will have the unique opportunity of appreciating the impact of natural cytotoxicity on primary tumours.

Publications

10 25 50

publication icon
Croy BA (2010) Analysis of uterine natural killer cells in mice. in Methods in molecular biology (Clifton, N.J.)

publication icon
Saudemont A (2010) A simple method to measure NK cell cytotoxicity in vivo. in Methods in molecular biology (Clifton, N.J.)

publication icon
Yadi H (2008) Unique receptor repertoire in mouse uterine NK cells. in Journal of immunology (Baltimore, Md. : 1950)

 
Description Project Grant
Amount £173,000 (GBP)
Organisation Association for International Cancer Research 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2011 
End 10/2013
 
Description Wellcome Trust Project Grant (Modulation of immune responses during haematopoietic cell transplantation)
Amount £400,000 (GBP)
Funding ID 088621 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2010 
End 05/2013
 
Title NK Cell Cytotoxicity 
Description A Simple Method to Measure NK Cell Cytotoxicity In Vivo 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact Natural cytotoxicity is considered an important parameter used to evaluate NK cell biology, both in the clinic and in the research lab. In this chapter we describe a simple method to quantify spontaneous NK cell cytotoxicity in vivo. 
 
Description Immune recognition of melanoma 
Organisation Babraham Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Melanoma recognition by NK cell receptors
Collaborator Contribution Provided insights and clinical materialProvided transgenic miceProvided insights, reagents and expertise in cell signallingProvided transgenic mice Provided transgenic mice
Impact Publication 19349689
Start Year 2007
 
Description Immune recognition of melanoma 
Organisation Claudius Regaud Hospital
Country France 
Sector Hospitals 
PI Contribution Melanoma recognition by NK cell receptors
Collaborator Contribution Provided insights and clinical materialProvided transgenic miceProvided insights, reagents and expertise in cell signallingProvided transgenic mice Provided transgenic mice
Impact Publication 19349689
Start Year 2007
 
Description Immune recognition of melanoma 
Organisation Institute of Cancer Research UK
Country United Kingdom 
Sector Academic/University 
PI Contribution Melanoma recognition by NK cell receptors
Collaborator Contribution Provided insights and clinical materialProvided transgenic miceProvided insights, reagents and expertise in cell signallingProvided transgenic mice Provided transgenic mice
Impact Publication 19349689
Start Year 2007
 
Description Immune recognition of melanoma 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution Melanoma recognition by NK cell receptors
Collaborator Contribution Provided insights and clinical materialProvided transgenic miceProvided insights, reagents and expertise in cell signallingProvided transgenic mice Provided transgenic mice
Impact Publication 19349689
Start Year 2007
 
Description Immune recognition of melanoma 
Organisation University of Ulm
Country Germany 
Sector Academic/University 
PI Contribution Melanoma recognition by NK cell receptors
Collaborator Contribution Provided insights and clinical materialProvided transgenic miceProvided insights, reagents and expertise in cell signallingProvided transgenic mice Provided transgenic mice
Impact Publication 19349689
Start Year 2007
 
Description Dissemination 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact We have published an article in "The Naked Scientist" and a student assay was shortlisted among the top 10 for the MRC Max Perutz Science writing competition 2007.

Public awareness of science
Year(s) Of Engagement Activity 2007,2008
 
Description Media coverage 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact The work done under this MRC grant was highlighted on the Babraham website as "paper of the month" in May 2009 and received media coverage, including an article in the Cambridge Evening News and BBSRC Business Magazine in January 2009.
Year(s) Of Engagement Activity 2009
 
Description Online seminar 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Policymakers/politicians
Results and Impact We presented our work in a Henry Stewart online seminar

Henry Stewart online seminars are accessed by a range of universities, medical schools, colleges, manufacturers, government agencies and service companies throughout the world.
Year(s) Of Engagement Activity 2009
 
Description School visits - Cambridge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Primary Audience Schools
Results and Impact Three visits to primary and secondary schools in the Cambridge area and participation to the Cambridge Science Festival in 2007.

School and public awareness of science
Year(s) Of Engagement Activity 2007,2008,2009