Regulation of T cell homeostasis by antigen receptor signals and interleukin-7

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

The Immune System plays a vital role in protecting individuals from parasitic infections by bacteria, viruses and other disease causing pathogens .T lymphocytes are immune cells that play a key role in regulating immune responses and having them in sufficient numbers is vital if they are to function properly. The number of T cells found in the immune system is carefully regulated by processes that control the production, survival and replication of T cells. Understanding how these processes work is important because when they go wrong, making too many T cells or the wrong type can cause autoimmune diseases such as diabetes or cause development of leukaemia or other cancers. Understanding how our bodies control T cell numbers are controlled also has clinical implications for developing treatments for conditions where T cell numbers are lost, for example in AIDS patients, for people undergoing cancer therapies which have the unwanted side affect of killing T cells or indeed for aiding reconstitution of bone transplant patients.All T cells express a surface protein, the T cell antigen receptor (TCR), that allows T cells to recognise and remember foreign pathogens. However, signals from this same receptor are also involved in controlling T cell survival and replication processes that are involved in controlling the size of the immune system. In addition, a soluble immune hormone, interleukin 7 (IL7) is also involved in regulating these same process and works together with TCR signals. The aim of our work is to gain a deeper understanding of how these two factors control the survival and replication of T cells. In order to do this, we have developed mouse models in which we can specifically control whether T cells receive signals from either the TCR or from IL7. By observing the behaviour and function of T cells in different situations, we can start to better understand how and when these factors are involved in controlling T cell numbers and how they can go wrong to cause disease

Technical Summary

The size and composition of the peripheral T cell compartment is remarkably stable in spite of constant production of new T cells from the thymus and during immune responses. This homeostasis is achieved through the highly specific regulation of survival, proliferation and death of T cells within the peripheral T cell compartment. What is more, the specific mechanisms that regulate homeostasis vary depending on T cell lineage (CD4 vs CD8) and states of differentiation (Naove vs memory). Cytokines and signals via the T cell antigen receptor (TCR) are among the chief environmental queues involved. In the latter case, TCR signals elicited by the recognition of self peptide-MHC complexes result in survival or cell division but not differentiation of T cells.The focus of the research within my group is to better understand how these signals contribute to the regulation of peripheral T cell homeostasis. To achieve this, we are developing novel mouse models that will permit genetic manipulation of the signalling pathways involved. To this end, we have developed mice that conditionally expression IL-7 receptor and Zap70, a key kinase in the transduction of TCR signals. With these models, we will be able to precisely quantify the contribution of these receptor signals to the homeostasis of the various subsets of peripheral T cells. They will also allow us to dissect the roles of the different signalling pathways downstream of these receptors and identify the genes whose expression is crucial for mediating homeostatic responses by T cells.

Publications

10 25 50
 
Description BBSRC/ANR joint project grant
Amount £420,673 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2008 
End 06/2011
 
Description US National Institute for Health/Einstein University as contractor to
Amount $1,761,637 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 04/2010 
End 03/2016
 
Title IL-7 genearray 
Description We have performed gene profiling of T cells receiving high, low or no IL7 signalling in order to identify IL7 regulated genes. This was achieved using the Affymetrix chip technology. 
Type Of Material Biological samples 
Year Produced 2008 
Provided To Others? Yes  
Impact We are currently analysing data. 
 
Title TetIL-7R mice 
Description We have generated a transgenic mouse model in which IL7 receptor expression is conditionally expressed in T lineage cells so as to better understand how IL7 regulates T cell homeostasis and function 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact We have identified a key role of IL7 in controlling the contraction phase of an immune response 
 
Title TetZap70 mice 
Description We have developed a transgenic mouse model in which the tyrosine kinase Zap70 can be conditionally expressed in the T cell lineage using the tetracycline inducible system. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2008 
Provided To Others? Yes  
Impact We are currently using it to analyse early events in positive selection of the T cell repertoire in the thymus. Switching on Zap70 transgene gene expression in mice lacking endogenous functional Zap70 restores thymic function that is otherwise blocked prior to positive selection. We can the examine the temporal regulation of thymic development of multiple T cell lineages. 
 
Description Applied statistical and mathematical modelling of peripheral T-Lymphocytes homeostasis 
Organisation National Institute of Health and Medical Research (INSERM)
Department INSERM U897 (Epidemiology and Biostatistics Research Centre)
Country France 
Sector Public 
PI Contribution The different teams are all involved in planning experiments and analysing data. Our group performs biological experiments, while our collaborators in France use the data to perform mathematical/statistical analysis
Collaborator Contribution Intellectual input as a member of the research team.They are part of a research collaboration.
Impact Initial findings from both Biological and Mathematical teams were presented at the first System's Immunology Workshop in Santa Fe, January 2010.
Start Year 2008
 
Description Applied statistical and mathematical modelling of peripheral T-Lymphocytes homeostasis 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution The different teams are all involved in planning experiments and analysing data. Our group performs biological experiments, while our collaborators in France use the data to perform mathematical/statistical analysis
Collaborator Contribution Intellectual input as a member of the research team.They are part of a research collaboration.
Impact Initial findings from both Biological and Mathematical teams were presented at the first System's Immunology Workshop in Santa Fe, January 2010.
Start Year 2008