Early growth protein molecules and preventing autoimmune disease and cancer

T lymphocytes are major part of white blood cells and play essential roles in protecting people from virus and bacterial infections. However, if over activated, T lymphocytes can attack normal tissues leading to the development of autoimmune diseases. Previously, we discovered an important mechanism mediated by molecule of a protein called early growth responsive 2 (Egr2) for preventing over activation of T lymphocytes. Importantly, we found a possible antagonistic function of Egr2 to T-bet, an inflammatory factor associated with autoimmune disease. However, the molecular mechanism of action by Egr2 on Tbet is still unknown which limits the translation of our findings into the development of novel relevant therapeutic strategies.

Based on our findings, we propose to investigate the mechanism of Egr2 using genetic modified mouse models established and analysing function of these cells and the importance in protection of autoimmune diseases.

We have developed unique models: Egr2 KO mice in which Egr2 removed from T lymphocytes, GFP-Egr2 mice in which Egr2 is linked with green fluorescent protein to visualise Egr2; GFP-Egr2/Amcyin-Tbet, in which in addition to GFP-Egr2, Tbet is linked with red fluorescent protein Amycin to visualise both Egr2 and Tbet in order to see how Egr2 interacts with Tbet in possible control of autoimmune disease.

By using unique mouse models, the objectives of this project and relevant impact are:

• To evaluate gene expressions of Egr2 and Tbet in order to find possible biomarkers in the diagnosis and prognosis of autoimmune diseases.
• To investigate the mechanisms how Egr2 regulates Tbet function for the development of therapeutic strategies in control autoimmune diseases.

Tumour infiltrated lymphocytes (TILs) contain tumour reactive T cells and have been used as adoptive cell transfer therapy in patients which can mediate cancer regression. However, without in vitro manipulation, TIL T cells are tolerant to tumour. Although it has been reported that PD1, a negative co-stimulatory molecule, could be induced highly in TIL T cells than T cells from peripheral, the intrinsic mechanisms for TIL T cells to resistant to tumour are largely unknown.

The aim of the project is to understand the mechanisms of Egr2 and 3 mediated T cell tolerance in tumour immunology. We will analyse the phenotype and function of Egr2 positive T cells in TILs using EG7 tumor model with GFP-Egr2 knockin mice; investigate what effects of Egr2/3 influence anti-tumour responses of T cells using Egr2/3 knockout and Egr2 overexpression transgenic mice; and understand how Egr2 and 3 expressions are regulated under tumour microenvironment, which may provide the potential bio-marks for tumour immune responses, and new strategy for individual immunotherapy of cancer patients.

Publications

• Zhu B., Symonds A.L.J, Martin JE., Kioussis D., Wraith D., Li SL and Wang P. Early growth response gene 2 (Egr-2) controls the self-tolerance of T cells and development of lupus like autoimmune disease. Vol. 205, 2295-2307, J Exp. Medicine, 2008.
• Suling Li, Tizong Miao, Meera Sebastian, Punamdip Bhullar, Emma Ghaffari, Mengya Liu, Alistair L. J. Symonds, and Ping Wang, Egr-2 and -3 are essential for both the control of inflammatory autoimmune diseases and antigen receptor mediated activation of B and T cells, Immunity,19;37(4):685-96, 2012.
• Miao, T., Symonds, A. L., Singh, R., Symonds, J. D., Ogbe, A., Omodho, B., Zhu, B., Li, S., Wang, P. Egr2 and 3 control adaptive immune responses by temporally uncoupling clonal expansion from T cell differentiation. Miao, T., Symonds, A. L., Singh, R., Symonds, J. D., Ogbe, A., Omodho, B., Zhu, B., Li, S., Wang, P. Egr2 and 3 control adaptive immune responses by temporally uncoupling clonal expansion from T cell differentiation. J Exp Med. 2017 Jun 5;214(6):1787-1808. doi: 10.1084/jem.20160553. Epub 2017 May 9.