............................................................................................................................... II ACKNOWLEDGEMENTS ..................................................................................................... IV TABLE OF CONTENTS ........................................................................................................... V LIST OF TABLES ................................................................................................................. VIII LIST OF FIGURES .................................................................................................................. IX LIST OF APPEDICES ............................................................................................................. XI LIST OF PUBLICATIONS AND PRESENTATIONS ........................................................ XII ABBREVIATIONS .................................................................................................................. XV CHAPTER 1: INTRODUCTION .............................................................................................. 2 PART I: THE CO-STIMULATORY TNFRSF MEMBER GITR .......................................................... 2 1.1. AN INTRODUCTION TO T CELL CO-STIMULATION AND THE TNFR FAMILY MEMBER GITR .. 2 1.2. EXPRESSION, REGULATION, AND STRUCTURAL FEATURES OF GITR AND GITRL ................ 3 1.3. INTRACELLULAR SIGNALING BY GITR ................................................................................. 4 1.4. STRUCTURE-FUNCTIONAL IMPLICATIONS OF GITR-GITRL INTERACTION ........................... 8 1.5. EFFECTS OF GITR-GITRL INTERACTIONS ON INNATE CELL SUBSETS .................................. 8 1.5.1. GITR-GITRL in innate inflammatory responses in vitro ............................................. 8 1.5.2. GITR-GITRL in leukocyte adhesion and migration .................................................... 9 1.5.3. Reverse signaling through GITRL in innate cells ..................................................... 10 1.5.4. Effect of GITR on NK and NKT cells ......................................................................... 11 1.6. THE ROLE OF GITR-GITRL ON B CELLS ........................................................................... 11 1.7. SIGNALING BY GITR ON REGULATORY AND CONVENTIONAL CD4 AND CD8 T CELLS. ..... 12 1.7.1. GITR co-stimulation of murine T cells ...................................................................... 12 1.7.2. Cross-regulation between GITR and other co-stimulatory molecules on T cells ...... 14 1.7.3. GITR co-stimulation of human T cells ....................................................................... 14 1.8. CELL-TYPE SPECIFIC EFFECTS OF GITR IN CANCER ............................................................ 15 1.8.1. GITR-targeted therapies for cancer .......................................................................... 15 1.8.2. Mechanisms of enhanced tumour immunity with GITR-targeted therapies .............. 16 1.8.3. GITR-GITRL in cancer immune evasion: modulating of NK and tumour cells ........ 17 1.9. GITR-GITRL IN INFLAMMATION, TRANSPLANTATION, ALLERGY, AND AUTOIMMUNITY ... 18 1.9.1. GITR-GITRL in inflammatory diseases ..................................................................... 18 1.9.2. GITR-GITRL in allergy ............................................................................................. 19 1.9.3. GITR-GITRL in models of colitis and autoimmunity ................................................. 19 1.9.4. Autoimmune models with Treg-extrinsic effects of GITR-GITRL ............................. 22 1.9.5. GITR-GITRL in tissue transplant models .................................................................. 23 1.9.6. Correlating GITR and GITRL expression in human autoimmune diseases .............. 24