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Early Growth Response Genes 2 and 3 Are Potent Inhibitors of T-Bet Function for Interferon Gamma Production in T Cells

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Early Growth Response Genes 2 and 3 Are Potent Inhibitors of T-Bet Function for Interferon Gamma Production in T Cells Early Growth Response genes 2 and 3 are potent inhibitors of T-bet function for Interferon Gamma production in T cells Randeep Singh Submitted for the PhD degree July 2016 Division of Biosciences College of Health and Life Sciences Brunel University London Declaration I hereby declare that the research presented in this thesis is my own work, except otherwise specified, and has not been submitted for any other degree. All illustrations have been adapted from the mentioned references and created and designed by myself in Microsoft Word and Power Point. SIINFEKL Tetramer staining and CFSE labelling and flow cytometry for these experiments was conducted by Professor Ping Wang. All work regarding maintaining the mice, administering virus, sacrificing mice and monitoring disease was done by Dr Su-ling Li at the animal facility, Brunel University London Randeep Singh 1 Abstract Early growth response (Egr) gene 2 and 3 are genes encoding transcription factors important for maintaining immune homeostasis. Here we define a fundamental role of Egr2 and 3 to control T cell proliferation and differentiation of effector T cells. Egr2 and Egr3 deficiency in T cells resulted in impaired T cell proliferation, but hyper-activation and excessive differentiation of T cells in response to viral infection, while, conversely, sustained Egr2 expression enhanced proliferation, but severely impaired effector differentiation in to T helper (Th) subsets, such as, Th1 and Th17 subtypes. T-bet is important for differentiation of effector T cells in response to pathogen and in particular it is a master regulator for modulating the T helper 1 lineage specific differentiation programme. Although T-bet has been extensively studied in T cells, the regulation of T-bet function is less well known. We have now discovered that Egr2 and 3 are potent inhibitors for T- bet function in CD4 and CD8 effector T cells. Together with Egr2 and 3, T-bet is induced in naïve T cells by antigen stimulation, but the expression was reciprocally regulated by IFNγ, which inhibited Egr2 and 3, but promoted T- bet expression. The expression of Egr2 and 3 in CD4 T cells under TH2 and TH17 condition was essential to suppress TH1 differentiation in vitro. In response to viral infection, sustained Egr2 expression in T cells profoundly inhibited differentiation of effector cells, while Egr2 and 3 deficient T cells produced excessive levels of IFNγ. We found that both Egr2 and 3 can directly interact with the Tbox domain of T-bet, block its DNA binding and inhibit T-bet mediated production of IFNγ. Thus, Egr2 and 3 are antagonists for T-bet function in effector T cells and essential for the control of T cell differentiation and immune pathology. 2 Acknowledgements A heartfelt thank you goes to my supervisors Professor Ping Wang and Dr Su-ling Li for their support, and I am forever grateful for Professor Wang’s belief in me and for Dr Su-ling Li for taking me on board this project. I owe a large debt of gratitude to Dr Tizong Miao and Dr Alistair J Symonds. Two talented and dynamic scientists, who I was privileged to work with and learn a great deal from. It has been a wonderful experience to work within a group that show immense commitment and focus in attaining scientific goals to the highest quality. They have been an inspiration to me throughout my Ph.D. and I feel fortunate to have been in their company. I would also like to thank Dr Punamdip Bhullar, Dr Ane Ogbe and Becky Omodho for their expertise whenever needed. I would also like to thank my work colleagues at Tesco where I have worked part-time during my Ph.D. I would like to extend my gratitude to Jamie Hedges for hiring me, because without this job, attaining this qualification would have been near impossible. Finally I would like to thank my mum, Kamaljit Kaur, brother Jagjeet (a.k.a. Captain Steve Rogers) and sisters Simran and Jas for their love and support. I am grateful for their encouragement in my decision to do this Ph.D. and their invaluable contribution towards it. I would particularly like to thank my mum for her blessings and being a truly wonderful human being. My mum has been my inspiration in life and has always been there to support me through all life’s challenges. Thank you all for sharing this journey with me. 3 Dedication This thesis is dedicated to my father the late Balvinder Singh Matharu, my mum Kamaljit Kaur Matharu and siblings, Simran, Jagjeet and Jasdeep and our lovely dog Ice. I hope this work can be an inspiration for everyone to pursue their dreams and believe anything is possible. Happy the man, and happy he alone He who can call today his own: He who, secure within, can say Tomorrow do thy worst, for I have lived today Be fair or foul or rain or shine The joys I have possessed, in spite of fate, are mine. Not heaven itself upon the past has power, But what has been, has been, and I have had my hour. By John Dryden 4 Table of Contents DECLARATION ................................................................................................... 1 ABSTRACT ......................................................................................................... 2 ACKNOWLEDGEMENTS ................................................................................... 3 DEDICATION ...................................................................................................... 4 LIST OF FIGURES ............................................................................................ 10 LIST OF TABLES .............................................................................................. 12 LIST OF ABBREVIATIONS ............................................................................... 13 Chapter 1 – INTRODUCTION .......................................................................... 16 1.1 The basic function of the Immune System .......................................... 17 1.1.1 Innate Immunity ........................................................................................ 17 1.1.2 Adaptive Immunity .................................................................................... 17 1.2 T Cell Immunology ................................................................................. 19 1.2.1 T cell development in the thymus ............................................................. 19 1.2.2 CD4-CD8- DN (Double Negative) to CD4+ and CD8+ SP (Single Positive) .......................................................................................................................... 19 1.2.3 T cell negative and positive selection ....................................................... 20 1.2.4 TCR and antigen presentation ................................................................. 22 1.2.5 Initiation and progression of TCR signaling .............................................. 23 1.2.6 DAG mediated signaling pathway ............................................................ 25 1.2.7 Ca2+ signaling pathway ............................................................................ 26 1.3 CD8 T cell mediated immune response ............................................... 27 1.3.1 CD8 T cell activation, differentiation and expansion ................................ 29 1.3.2 CTL contraction and memory formation ................................................... 31 1.3.3 Central (TCM) and Effector (TEM) memory ................................................. 32 1.4 CD4 T cells .............................................................................................. 33 1.4.1 CD4 T helper differentiation ..................................................................... 34 1.4.2 T-bet and T helper 1 (TH1) cells ............................................................... 35 1.4.3 GATA3 and T helper 2 (TH2) cells ............................................................ 37 1.4.4 RORγt T helper 17 (TH17) cells ................................................................ 38 1.4.5 Bcl6 and T follicular helper (Tfh) cells ....................................................... 39 5 1.4.6 Foxp3 and Regulator T (TReg)cells ........................................................... 40 1.5 Cytokines ................................................................................................ 42 1.5.1 Interferon Gamma (IFNγ): A type I interferon ........................................... 47 1.5.2 IFNγ and its receptor ................................................................................ 48 1.5.3 IFNγ signaling in T cells ........................................................................... 48 1.5.4 Regulation of IFNγ in T cells .................................................................... 49 1.5.5 IFNγ in disease ......................................................................................... 52 1.6 Early Growth Response (Egr) genes .................................................... 53 1.6.1 Egr protein structure ................................................................................. 55 1.6.2 Egr DNA binding ....................................................................................... 54 1.6.3 Egr proteins function outside the immune system .................................... 54 1.6.4 Egr proteins in T cells ............................................................................... 55 1.6.5 Egr protein in autoimmunity ...................................................................... 57 1.7 Egr2 and 3 conditional knockout mouse model .................................. 58 1.7.1
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