Investigation of the early growth response gene (Egr) 2 and 3 mediated regulatory programme in T cells

Our heath relies on the normal function of the immune system. The function of the immune system is uniquely regulated in such a way that it can maintain a robust attack against pathogens, such as viruses, but remain tolerant of one's own tissues. Although the function of the immune system has been extensively studied, the mechanisms which cause the immune system to mistakenly attack one's own body or to permit the persistence of certain viruses, such as HIV, in our body are still unknown. More than 80 clinically distinct autoimmune diseases result from dysregulation of the immune system. Several are well known, including rheumatoid arthritis, multiple sclerosis, type 1 diabetes, and lupus. Others are less familiar, including autoimmune hepatitis, Sjögren's syndrome, autoimmune ear disease, and pemphigus. Equally, more than 10 chronic infectious diseases, such as HIV and hepatitis C virus infection, result from a failure of our immune system to provide protection. Collectively, these diseases afflict an estimated 5 to 8 per cent of the population in the UK and worldwide. The social and financial burdens imposed by these chronic, debilitating diseases include poor quality of life, high health care costs, and substantial loss of productivity. Recently we discovered a unique function of two molecules, Egr2 and 3, in one type of white blood cells, T cells, which is essential for preventing the immune system from attacking self-tissues while promoting immune attacks on viruses. Removal of these two molecules from T cells from mice results in severe autoimmune diseases that are similar to human lupus diseases and these mice also fail to recover from virus infection. These findings were previously unknown and have been published in leading immunological journals such as 'The Journal of Immunology', 'The Journal of Experimental Medicine' and 'Immunity'. The proposed study aims to define the mechanisms by which Egr2 and 3 prevent T cells from attacking self-tissues but enhance their anti-virus function. The findings from the proposed study would not only provide a better conceptual understanding of immunological function, but importantly provide new strategies for the development of therapies for autoimmune and chronic infectious diseases.

Clonal expansion and differentiation of effector cells are hallmarks of T cell responses against virus infection. Dysregulated expansion and/or differentiation can result in chronic infection, autoimmunity and severe immunopathology. We have discovered that the transcription factors Egr2 and 3 have an overlapping function in promoting clonal expansion, but restraining differentiation of effector T cells, in response to virus infection and also suppressing inflammatory responses of self-reactive T cells under homeostatic conditions. Defects in both Egr2 and 3, but not single Egr2 or 3 deficiency, in T cells results in defective anti-viral responses with high inflammation which resembles the altered T cell function in chronic infectious. Intriguingly, T cells in autoimmune disease also have a poorly proliferative, but highly inflammatory, phenotype. We found that Egr2 and 3 are only expressed in a subpopulation of CD44high T cells. Using our models of CD2-Egr2Ko, CD2-Egr2/3Ko, CD2-Egr2 transgenic and GFP-Egr2 knockin mice, as well as Egr3Ko, we will dissect the mechanisms of Egr2 and 3 function in T cells and investigate; the function of Egr2 and/or 3 expressing T cells in homeostatic and anti-viral responses, the mechanisms of Egr2 and 3 function in effector T cells for reciprocal regulation of proliferation and differentiation during anti-viral responses, and the molecular programmes regulating Egr2 and 3 expression in effector T cells under homeostatic conditions and during anti-viral responses. The results will impact not only on our understanding of T cell responses, but may also provide mechanisms underlying dysregulated immunoresponses in chronic infection and autoimmune diseases.

Autoimmune and chronic infectious diseases are the most significant health problems in western civilisations and have an enormous impact on the wellbeing and economy of the UK. The proposed research although basic-research oriented will have several beneficiaries in both the understanding of basic immunoresponses and clinical applications for diagnosis and new therapeutics of autoimmune and/or chronic infectious diseases. The advance in knowledge on the control of T cell function will be of great value to the academic community, and the animal models, the new methodologies and approach proposed within the project will be a valuable assess to the wider discipline of basic and clinical immunological researches.
The overall question of understanding the fundamental mechanisms for balancing self-tolerance and anti-pathogenic immunoresponses has also great impact to the general public. T cells dictate immune system for self-tolerance and optimal anti-pathogenic responses. Alteration of T cell function, both under and over responses, can affect either the development of autoimmune diseases and impaired anti-infection. Therefore the insight mechanisms controlling T cell response to self-tissues or pathogens such as virus are fundaments for the development of treatments for autoimmune and chronic infectious diseases. This will help the pharmaceutical industry to direct resources toward the right target for the development of suitable treatments and clinician to use as markers for early diagnosis. Such advances will be of direct benefit to the general population both in terms of health, well-being, and indirectly on the socio-economic wealth.
This particular study will also have direct impacts for the Pharmaceutical and Biotechnology industries. It is well known that immune modulators that are able to suppress or enhance T cell function are widely used in autoimmune and chronic infectious diseases. Despite their importance, the effects of these reagents are often difficult to monitor due to lack of markers indicating the function of responding T cells. Therefore the identification of molecules with potential as either druggable target or clinical markers is extremely important. Transcription factors do not directly involve in the function of T cells, but they direct the molecular programmes that execute the function of responding T cells for either effectively response or maintaining tolerance to antigens. Therefore, the molecules regulated by transcription factors under tolerant or anti-pathogen responses are potential drug targets. The targets of Egr2 and 3 in T cells will be selected to feed the Pharmaceutical companies for the development of immune modulators.
Finally, the dissemination of the findings to the general public will produce a more public awareness on the importance of the basic science investigations for the improvement of public health and the generation of wealth within the country and worldwide.