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The Role of Fc Receptor-Like 6 in Innate and Adaptive Immunity

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The Role of Fc Receptor-Like 6 in Innate and Adaptive Immunity The role of Fc receptor-like 6 in innate and adaptive immunity Yash Patel University College London and The Francis Crick Institute PhD Supervisor: Dr George Kassiotis A thesis submitted for the degree of Doctor of Philosophy University College London September 2019 Declaration I Yash Patel, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract……. Fc receptor-like 6 (FCRL6) is an immunoreceptor tyrosine-based inhibitory motif-bearing transmembrane receptor upregulated on human cytotoxic T and NK cells during chronic immune activation. It has been suggested to act as an inhibitory receptor by possibly interacting with human leukocyte antigen-DR (HLA-DR), but its function remains largely unknown. We initially investigated the role of FCRL6 in T cells using its murine counterpart. However, Fcrl6 expression was absent in developing, mature or activated mouse T cells. Therefore, we generated a human FCRL6 (hFCRL6) expressing transgenic mouse to investigate the function of this receptor. The expression of HLA-DR on antigen presenting cells resulted in reduced in vitro proliferation of hFCRL6+ CD4+ T cells. However, we were unable to recapitulate this inhibitory effect of the hFCRL6:HLA-DR axis in an in vivo environment. Further characterisation of mouse immune populations revealed Fcrl6 expression in natural killer (NK) and developing B cells. Analysis of Fcrl6-/- mice showed that the development of these cells as well as T cells and the splenic proportion of most major immune populations remained unaffected by FCRL6 deletion. We observed a reduction in the proportion of splenic macrophages and NK cells in Fcrl6-/- and NK conditional Fcrl6-/- mice, respectively. However, NK cell responses in a chronic retroviral infection model as well as a tumour model remained unaffected by FCRL6 deletion. Similarly, B cell antibody production in response to retroviral infection was also unaffected by FCRL6 deletion. Overall, data obtained here suggested that the mouse ortholog of FCRL6 might not possess the potential immunoregulatory capacity of its human counterpart and thus may have evolved to mediate non-immunoregulatory functions. Further studies will be required to define the role of mouse FCRL6 in NK cells and macrophages in addition to hFCRL6 in NK cells and T cells. 3 Impact Statement The findings from my thesis suggested that mouse and human FCRL6 may mediate distinct functions in their respective species. Consequently, this should be considered when attributing possible functions of mouse FCRL6 to its human counterpart. The data in my thesis also suggested that human FCRL6 might possess inhibitory functionality as evidenced by reduced in vitro proliferation of human FCRL6 expressing mouse CD4+ T cells. However, further studies will be required to confirm this finding, elucidate the underlying mechanism and precisely define the circumstances where this receptor might play a potential inhibitory role in the human immune system. An increased understanding of the function of human FCRL6 may allow for the development of novel therapeutics that could improve our immunotherapy-based arsenal against infectious disease, cancer and autoimmunity. 4 Acknowledgement Firstly, I would like to express my deepest gratitude to my supervisor, Professor George Kassiotis, for his continuous support, patience and immense knowledge. I appreciate his contribution of time and ideas to make my PhD experience both productive and stimulating. The past and present members of the Kassiotis group have contributed greatly to my scientific development and for this I cannot thank them enough. I am especially grateful to Dr Luca Danelli for his willingness to discuss my research and for providing me with valuable feedback. I would also like to thank Dr Jan Attig and Nikhil Faulkner for their continuous support in the lab but mostly for the Waitrose walks! Lastly, I am grateful to my family who have always pushed me to fulfil my potential and so I would like to dedicate this work to my loving parents, Prakash and Dina Patel, and my sister, Shachi Patel for their words of encouragement and unrelenting support. 5 Table of Contents Abstract……………………………………………………………………………….. 3 Impact Statement ............................................................................................. 4 Acknowledgement............................................................................................ 5 Table of Contents ............................................................................................. 6 Table of figures............................................................................................... 10 List of tables.................................................................................................... 13 Abbreviations ................................................................................................. 14 Chapter 1.Introduction ................................................................................... 17 1.1 The immune system ............................................................................. 17 1.1.1 Innate immunity ................................................................................ 17 1.1.2 Adaptive immunity ............................................................................ 20 1.2 Regulation of the immune response ................................................... 21 1.2.1 Regulation by competitive antagonism ............................................. 21 1.2.2 Regulation by ubiquitin ..................................................................... 22 1.2.3 Regulation by intracellular negative regulators ................................. 23 1.2.4 Regulation by receptor downregulation ............................................ 23 1.2.5 Regulation by immunoreceptor tyrosine-based motifs ...................... 24 1.2.6 Inhibitory receptors expressed by lymphocytes ................................ 26 1.2.6.1 B cell expressed inhibitory receptors ................................................................27 1.2.6.2 T cell expressed inhibitory receptors ................................................................28 1.2.7 Functional exhaustion of T cells ....................................................... 30 1.2.8 Therapeutic potential of inhibitory receptor blockade........................ 32 1.3 Fc receptor-like proteins ...................................................................... 34 1.3.1 Discovery .......................................................................................... 34 1.3.2 Genomic location in humans and mice ............................................. 36 1.3.3 Relation to classical Fc receptors ..................................................... 38 1.3.4 Conservation across different species .............................................. 38 1.3.5 Structure of the human and mouse FCRL protein family .................. 39 1.4 Fc receptor-like 6 .................................................................................. 41 1.4.1 Isoforms ............................................................................................ 41 1.4.2 Intracellular signalling ....................................................................... 43 1.4.3 Expression ........................................................................................ 44 1.4.4 Ligands ............................................................................................. 47 1.4.5 Function ............................................................................................ 47 1.5 Friend virus ........................................................................................... 49 1.5.1 The Friend Virus Model .................................................................... 49 1.5.2 Immune response to Friend virus ..................................................... 49 1.5.2.1 T cell mediated responses ...............................................................................49 1.5.2.2 NK cell mediated responses ............................................................................51 1.5.2.3 B cell mediated responses ...............................................................................51 1.6 B16 melanoma ...................................................................................... 53 1.6.1 NK mediated immune response to B16 melanoma cells .................. 53 1.7 Aims and hypothesis ............................................................................ 55 Chapter 2.Materials & Methods ..................................................................... 56 2.1 Mice ........................................................................................................ 56 6 2.1.1 Generation of Fcrl6-/- mice ................................................................ 57 2.1.2 Generation of transgenic mice .......................................................... 57 2.1.2.1 EF4.1 mice ......................................................................................................57 2.1.2.2 Human FCRL6 transgenic mice .......................................................................57 2.2 Tissue and cell preparation ................................................................. 58 2.2.1 Media and culture conditions ............................................................ 58 2.2.2 Single cell suspensions ...................................................................
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