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

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.

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.