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

Lead Research Organisation: University College London

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

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Hogan T (2013) Clonally diverse T cell homeostasis is maintained by a common program of cell-cycle control. in Journal of immunology (Baltimore, Md. : 1950)

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Hogan T (2015) Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice. in Proceedings of the National Academy of Sciences of the United States of America

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Marshall D (2014) Differential requirement for IL-2 and IL-15 during bifurcated development of thymic regulatory T cells. in Journal of immunology (Baltimore, Md. : 1950)

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Schim Van Der Loeff I (2014) Zap70 is essential for long-term survival of naive CD8 T cells. in Journal of immunology (Baltimore, Md. : 1950)

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Silva A (2014) NF-?B signaling mediates homeostatic maturation of new T cells. in Proceedings of the National Academy of Sciences of the United States of America

 
Description NIH RO1
Amount $1,700,000 (USD)
Organisation National Institutes of Health Clinical Center 
Sector Hospitals
Country United States
Start 03/2016 
End 02/2021
 
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 floxed reporter mouse 
Description A mouse in which exons 2 and 3 of IL-7 gene are flanked by loxP sites and express LacZ gene in their place 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Initiation of projects to investigate expression and function of IL-7 in a mature immune system 
 
Title Tet inducible Rag1 transgenic mouse 
Description A transgenic mouse model in which Rag1 recombinase gene is under control of a Tetracycline inducible promotor 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Initiation of new project to investigate mechanisms of new T cell maturation 
 
Description Yates Seddon maths 
Organisation Columbia University
Country United States 
Sector Academic/University 
PI Contribution We are subcontractors to an NIH grant held by Professor Andrew Yates
Collaborator Contribution The laboratory of Andrew Yates undertakes computational analysis of biological data generated by our laboratory, with the aim of better understanding the homeostasis and maintenance of lymphocyte populations throughout the life course
Impact Papers
Start Year 2016