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The Role of Killer Immunoglobulin-Like Receptors In The role of killer immunoglobulin-like receptors in HTLV-1 infection A thesis submitted to Imperial College London for the degree of Doctor of Philosophy By Katie R. Twigger Imperial College London 2014 Section of Immunology Department of Medicine Wright-Fleming Institute Imperial College Norfolk Place London W2 1PG Declaration of originality and copyright Copyright The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution-Non Commercial-No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or distribution, researchers must make clear to others the licence terms of this work. Declaration of originality All work presented in this thesis is the author’s own other than where clearly stated in the ‘Statement of Collaboration’. Signature________________ Date____________________ 2 Summary Human T-lymphotropic virus type 1 (HTLV-1) causes the debilitating neuroinflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a minority of infected individuals, while the majority are lifelong asymptomatic carriers (ACs). The effectiveness of the CD8+ T-cell response to HTLV-1 is a major determinant of the HTLV-1 proviral load (PVL) and the associated HAM/TSP risk. Host genotype, particularly of HLA class I, strongly influences CD8+ T-cell effectiveness against HTLV-1. Furthermore, possession of the KIR gene 2DL2 was recently shown to enhance protective and detrimental HLA class I-associated immunity to HTLV-1 and HCV (Seich al Basatena et al., 2011). The proposed mechanism explaining this effect is a KIR expression-induced increase in activation thresholds, thus promoting survival. I investigated KIR expression and function on T-cells and NK cells in HTLV-1 infection, focussing on CD8+ T-cells and using new anti-KIR mAbs to analyse 2DL2 expression alongside four other KIRs. This thesis presents evidence supporting the genetic findings and the KIR expression-induced CD8+ T-cell survival hypothesis. AC status was associated with expanded 2DL2+CD8+ T EM cell populations and 2DL2+ and 2DL3+CD8+ T EM cell frequencies were inversely correlated with PVL, consistent with a protective role for 2DL2 (and potentially 2DL3) expression on CD8+ T-cells in HTLV- 1 infection. Rather than a generalised reduction in CD8+ T-cell function, specific KIR expression was associated with a shift in effector function profile towards a cytotoxic phenotype without cytokine production. This is consistent with raised activation thresholds and may suggest fine-tuning of CD8+ T-cell effector functions by KIRs, preserving killing without causing inflammation. I further speculate that 2DL2/3 could be a context-dependent modulator of CD8+ T-cell function, optimally tuning responses and contributing to CD8+ T-cell effectiveness. Together with the longevity of 2DL2/3+CD8+ T-cells in vivo, this hypothesis requires further testing, since it may be relevant to other persistent viral infections. 3 Acknowledgements Firstly, I would like to thank my supervisors Keith Gould and Charles Bangham for their supervision, guidance and advice. I would also like to thank the members of the Immunology Department at St Mary’s for all their help, technical training, teaching and discussion on all things HTLV-1, in particularly Aileen Rowan, also Katerina Seich al Basatena, Heather Niederer, Anat Melamed, Lucy Cook, Danny Laydon and Hiroko Yaguchi. I am also grateful to the Wellcome Trust for my funding. I am very grateful to all of the patients at the National Centre for Human Retrovirology who donated blood for this study, and all the people who provided control samples for me. I would like to thank Graham Taylor and his team for all their help with this. This study would not have been possible without the assistance of my collaborators. I am very grateful to Christelle Retiere and Gaelle David for kind provision of their anti-KIR mAbs and for their advice on using these reagents. I would also like to sincerely thank James Traherne for all his help with understanding the complex world of KIR genotyping and alloypting, and also Olympe Chazara. I am also very grateful to the following for flow cytometry advice: Andrea Stacey, Seph Borrow, Kalle Malmberg, Vivian Beziat, Thurka Poobalasingam and Suzanne Venables. I would like to say a big thank you to all at the ICR, past and present, for getting me started with this science thing, and inspiring and encouraging me to go further, particularly Kevin Harrington, Christine White and Virginie Mieulet, also Vickie Roulstone, Katie Copeland, Rohit Seth, the Targeted Therapy Team, the Marais and Marshall labs. Also thanks to my Wellcome Trust Programme cohort, especially Sorcha Cassidy and Anna Cauldwell for your encouragement. Thank you to my amazing friends and family for all your support, particularly to my mum Roselyn Twigger, for your complete and unwavering belief in me and especially for looking after me while I was writing, and my dad Brian Twigger, for your extremely high standard of proof-reading. Finally and most of all, to my wonderful husband Alex Miller, thank you so much for supporting me throughout this experience, I honestly could not have done this without you. 4 Table of Contents Declaration of originality and copyright ............................................................................ 2 Summary ..... ....................................................................................................................... 3 Acknowledgements ............................................................................................................ 4 Table of Contents ................................................................................................................ 5 List of Figures ..................................................................................................................... 8 List of Tables ..................................................................................................................... 10 List of abbreviations ......................................................................................................... 11 Statement of collaboration ............................................................................................... 13 Chapter 1. Introduction ..................................................................................................... 14 1.1 HTLV-1 epidemiology and transmission ........................................................................ 15 1.2 HTLV-1-associated diseases ........................................................................................... 17 1.2.1 HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)..................... 17 1.2.2 Adult T cell leukaemia/lymphoma (ATLL) .................................................................... 19 1.2.3 HTLV-1 associated inflammatory/autoimmune diseases and co-infections .................. 20 1.3 Cellular and molecular biology ....................................................................................... 21 1.3.1 Initial infection and integration ..................................................................................... 21 1.3.2 Viral gene expression ................................................................................................. 22 1.3.3 Mechanisms of viral proliferation and persistence ....................................................... 26 1.4 Proviral load and the risk of disease .............................................................................. 28 1.5 Immune response to HTLV-1........................................................................................... 29 1.5.1 CD8+ T cells ............................................................................................................... 29 1.5.2 CD4+ T cells ............................................................................................................... 34 1.5.3 NK cells and innate immunity ...................................................................................... 36 1.5.4 Antibodies .................................................................................................................. 37 1.6 Killer immunoglobulin-like receptors (KIRs) .................................................................. 38 1.6.1 Molecular structure ..................................................................................................... 38 1.6.2 KIR ligand specificities ................................................................................................ 41 1.6.3 Genetic features ......................................................................................................... 43 1.6.4 Cellular expression of KIRs on NK cells and T cells..................................................... 47 1.6.5 Function of KIRs on NK cells and T cells ..................................................................... 49 1.7 KIR associations with disease ........................................................................................ 51 1.7.1 Viral infections ............................................................................................................ 51 1.7.2 Autoimmune/inflammatory conditions .......................................................................... 55 1.8 KIRs in HTLV-1 immunity
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