PI3K signalling in regulatory T cells.

Lead Research Organisation: University of Birmingham
Department Name: Immunity and Infection

Abstract

Our immune system protects us from infection by pathogens such as viruses, bacteria and parasites. As with any defence mechanism, the risk of collateral damage is unavoidable. The immune system uses several different strategies to limit the damage to the host. T cells (a type of white blood cell) play a central role in orchestrating immune responses, in the killing of infected cells and in the maintenance of immunological memory (the basis for vaccines). Each T cell that develops has a unique receptor on the surface that can bind to components of pathogens and hence recognise their presence. Each T cell expresses a unique, randomly generated specificity for such recognition. There is of course always a potential for such receptors to recognise different organs in the body. To avoid overt attacks on the body's organs, T cells with strong self-reactivity are eliminated during development. However, some self-reactive T cells escape this elimination process and need to be kept in check. Recently, a subgroup of T cells / called regulatory T cells (Tregs) / has been identified. These T cells are self-reactive, but instead of initiating immune responses, they suppress the function of potentially destructive T cells. Individuals who lack this population of T cells die young from a devastating attack on different organs in the body. There is great interest in learning more about how the Tregs work. In particular, scientists want to know if they can harness the power of Tregs to protect against autoimmune diseases such as arthritis, diabetes and multiple sclerosis. In addition, pharmaceutical companies developing drugs against normal T cells that cause autoimmune diseases, want to avoid inhibiting the function of Tregs. PI 3-kinases are enzymes that relay information from outside the cell to the cell nucleus, allowing the cell to make decisions based on environmental cues. When a T cell recognises a component of a pathogen, the PI 3-kinase pathway is activated and influences the type of immune response that ensues. By inhibiting PI 3-kinases, certain harmful immune responses may be averted. Pharmaceutical companies are therefore currently developing and testing dugs against p110delta, the type of PI 3-kinase expressed in T cells (but not by cells in the major organs). We have found, using mice in which PI 3-kinase activity in T cells has been blocked genetically, that Tregs are unable to block the function of conventional T cells. This could be a serious disadvantage for the development of drugs against p110delta and needs to be investigated further. To this end, we intend to identify genes that may be affected by the lack of PI 3-kinase activity in Tregs. This will help us better understand precisely how p110delta inhibition may affect Tregs, but may also help us identify other genes that are required for Treg function; most of these are currently unknown. We will also examine how p110delta contributes to the development of regulatory T cells during an immune response. Most of the experiments to date were performed with cell cultures and do not necessarily fully reflect the role of Tregs during an autoimmune attack. To examine this aspect further, the capacity of p110delta-deficient Tregs to protect against autoimmune diabetes will be examined. This requires a more complex network of cellular interactions and it will be important to map the precise defects of p110delta-deficient T cells in this context. Finally, we will delete the gene for p110delta specifically in Tregs. This experiment will reveal definitively whether p110delta in Tregs is essential for keeping the rest of the immune system in check. The benefit of this research is that we will gain a greater understanding of the genes and molecules that control the life-saving properties of Tregs. In addition, this research will help inform pharmaceutical companies about the advantages, as well as potential dangers, associated with drugs that target p110delta.

Technical Summary

PI3Ks play diverse roles in all mammalian cells, ranging from the regulation of metabolism to migration, differentiation, survival and gene expression. We have previously shown that the PI3K p110delta plays a key role in regulating helper T cell proliferation and differentiation. In the course of these studies, we noted that a different subset of T cells, so-called regulatory T cells (Tregs), is incapacitated in mice lacking p110delta activity. From a functional point of view, Tregs have been shown to play an essential role in preventing the immune system from turning against its host. Mice or human beings that lack Tregs die young as the consequence of violent autoimmune responses. Nonetheless, as a defined T cell subset, Tregs have only recently been characterised based on their expression of CD25 and Foxp3. Although a number of genes required for their differentiation and homeostasis have been identified, understanding of the molecular basis for Treg-mediated suppressive function is limited. The goal of this grant is to investigate the role of the PI3K p110delta on Tregs and thus to determine the molecular basis for Treg-mediated suppression of T cell function. Tregs have the unique capacity to block the expansion of Th cells. We have found that p110delta-deficient Tregs lack this capacity. The purpose of this grant is to extend these finding by examining the genes regulated by p110delta in T cells. We will also investigate the role of p110delta during the conversion of peripheral T cells to Tregs. We will interrogate the potential for p110delta-deficient Tregs to prevent autoimmune diabetes. Finally, we will determine the effect of selective elimination of p110delta in Tregs. These studies will help define the contribution of p110delta to Treg function, a question of great interest to pharmaceutical companies that are developing p110delta inhibitors. In addition, the molecular basis underlying Treg-mediated suppression will be elucidated further.

Publications

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Description Our experiments provided new information on the role of a particular enzyme in regulation of immune responses. We identified roles for this enzyme (PI3K-p110delta) in regulatory T cells, a subset of white blood cells that inhibit unwanted immune responses. This information was critical in moving the field forward and underpinned a recent Nature paper [PMID 24919154] suggesting that pharmacological inhibition of this enzyme could be beneficial in cancer.

More recently we showed that the PI3K-p110delta enzyme also plays roles in immune cells called B cells that are important in making antibodies. This provides greater insight into the breadth of functions performed by this enzyme.
Exploitation Route These findings have already been taken forward and there is now considerable momentum to target this enzyme pathway therapeutically.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Our experiments provided new information on the role of a particular enzyme in regulation of immune responses. We identified roles for this enzyme (PI3K-p110delta) in regulatory T cells, a subset of white blood cells that inhibit unwanted immune responses. This information was critical in moving the field forward and underpinned a recent Nature paper [PMID 24919154] suggesting that pharmacological inhibition of this enzyme could be beneficial in cancer.
Sector Healthcare,Pharmaceuticals and Medical Biotechnology