Regulation of T cell homeostasis by antigen receptor signals and interleukin-7
Lead Research Organisation:
University College London
Department Name: UNLISTED
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.
People |
ORCID iD |
Publications
Sinclair C
(2013)
Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system
in Proceedings of the National Academy of Sciences
Hawkins ED
(2013)
Regulation of asymmetric cell division and polarity by Scribble is not required for humoral immunity.
in Nature communications
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)
Bains I
(2013)
Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection.
in PLoS computational biology
Hogan T
(2014)
Spatial Heterogeneity and Peptide Availability Determine CTL Killing Efficiency In Vivo
in PLoS Computational Biology
Ayoub H
(2014)
Parameter identification for model of T cell proliferation in Lymphopenia conditions
in Mathematical Biosciences
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)
Sinclair C
(2014)
Overlapping and Asymmetric Functions of TCR Signaling during Thymic Selection of CD4 and CD8 Lineages
in The Journal of Immunology
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)
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 | 03/2010 |
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 |