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Innate Immune Pathways in the Draining Lymph Node

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Innate Immune Pathways in the Draining Lymph Node Innate Immune Pathways in the Draining Lymph Node James Arrich University College London (UCL) Division of Medicine Centre for Clinical Pharmacology Rayne Institute London This thesis is submitted for the degree of Doctor of Philosophy 2020 1 Declaration I, James Arrich 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. Chester, July 2020 2 Abstract The draining lymph node (dLN) is the anatomical site in which adaptive immune responses are initiated following vaccination. It is increasingly recognised that the dLN also serves an important innate barrier function and that inflammatory stimuli (including vaccine adjuvants) drive cardinal aspects of the innate immune response within the dLN. The characterisation of these intranodal innate immune processes and their impact upon the concurrently developing adaptive immune response is therefore central to the design of novel vaccines and adjuvants. Neutrophil and monocyte infiltration is a cardinal feature of the innate immune response. This phenomenon is studied within the dLN in the context of two key innate immune pathways; cyclooxygenase-dependent prostanoids and type I interferons. These processes were studied using a murine skin immunisation model following challenge with killed E. coli (KEC), which induced the rapid and sequential infiltration of neutrophils and monocytes into the dLN. These infiltrating myeloid cells were major expressers of cardinal prostanoid synthases (cyclooxygenase-2, microsomal PGE synthase-1 and thromboxane synthase), as well as important interferon-stimulated genes such as CXCL9 and CXCL10. Notably, cyclooxygenase inhibition during their infiltration did not modulate the developing humoral immune response. In contrast, type 1 interferons drove the differential upregulation of CD69 by different lymphocyte subsets and the acute production of interferon-γ by dLN NK cells; processes that play important roles in the retention and activation of T cells. In vitro evidence suggests that these processes are driven by interferon-stimulated monocytes, a hypothesis supported by the markedly increased expression of type I interferon stimulated genes by dLN monocytes in vivo. In conclusion, this thesis highlights the role of infiltrating myeloid cells as unappreciated orchestrators of type I interferon-driven innate immune pathways in the dLN. This finding informs hypotheses that assert that inflammatory monocytes drive Th1 T cell responses in the dLN. 3 Impact Statement The field of vaccine research has rarely seemed more pertinent than in the light of the COVID- 19 pandemic. This thesis contributes to this crucial field as it presents data that informs vaccine adjuvant design. Adjuvants serve to increase the immunogenicity of the antigen(s) within a vaccine formulation. However, until recently, adjuvant design was a relatively neglected field of research, with only two adjuvants currently listed in the UK immunisation regimen. It is increasingly recognised that adjuvants work in part by engaging the innate immune system directly within the draining lymph node (dLN). It is by characterising and delineating these intranodal innate immune pathways that this thesis contributes to this expanding field. This thesis demonstrates that neutrophils and monocytes (both key effector cells of the innate immune system) infiltrate the dLN in large numbers following a murine skin challenge with killed E. coli bacteria (KEC). Moreover, these infiltrating myeloid cells demonstrated markedly elevated expression of genes that drive the innate immune response, including synthases that manufacture inflammatory prostanoids and a range of type 1 interferon-stimulated genes (ISGs). Type 1 interferons were shown to play important roles in driving the differential upregulation of CD69 by different lymphocyte subsets as well as inducing the production of IFNγ by NK cells. These processes are important for the retention and activation of T cells within the dLN. The fact that monocytes in particular are major expressers of ISGs suggests that monocytes orchestrate these processes within the dLN. This thesis therefore highlights interferon-activated monocytes as key cells that potentially orchestrate the induction of T cell responses and are thus an important target for future adjuvant research. Indeed, this thesis poses several hypotheses that address how monocytes may mediate such a function and sets out the methods by which these hypotheses could be tested. Moreover, efforts have been made to disseminate the findings of this thesis to the wider scientific community. In this regard, data from this thesis has been presented at both university and national conferences in poster format (the British Society of Immunology Congress 2017 and the UCL Division of Medicine Conference 2018) and is planned to be submitted for publication in peer-reviewed academic journals. Finally, the fact that the aforementioned processes are studied in the context of a challenge with KEC is also of wider significance. Laboratories within the UCL Division of Medicine have pioneered the use of KEC to study acute inflammation in the skin of healthy human volunteers. The intradermal murine immunisation model established in this thesis therefore provides a platform that can be readily adopted to undertake parallel studies of this inflammatory 4 stimulus in humans and mice. Furthermore, this thesis demonstrates that aspects of the innate immune response to KEC mirror that of novel TLR4-agonist adjuvants such as AS01 and GLA-SE. The direct comparison of KEC with these adjuvants in mice and/or humans may therefore reveal important differences in the immune response that could inform future adjuvant design. 5 Acknowledgements I would like to express sincere thanks and gratitude to my supervisor Professor Derek Gilroy for providing me with continuous guidance and feedback throughout the project. I would also like to thank my secondary supervisor Professor Arne Akbar and my tutors in the MBPhD programme (Professor Raymond MacAllister, Professor Robert Unwin and Dr Daniel Marks) for their advice and support at times of concern. I would like to thank Dr Andreas Wack for the provision of IFNAR-deficient mice and guidance with regard to the study of type I interferons, and Dr Mark Coles for sharing data that informed experiments conducted in this thesis. To all members of the Gilroy lab (past and present), it has been a joy to work with you over the past 6 years and I would like to thank you all for your guidance, support and friendship. I would like to thank Dr Justine Newson for her patience when teaching me the practical side of biomedical research and Dr Roel De Maeyer for continually challenging my assumptions with a kind but critical ear. Finally, I would like to especially thank Dr Rachel Van de Merwe, you went the extra mile when you saw I was struggling. Specific thanks must also be extended to Dr Pascal Durrenberger and David Pearce for teaching me how to perform immunohistochemistry as well as Dr Helina-Elaine Marshall, Dr Meera Mehta and Dr Gabriel Pollara for microbiological guidance. Similarly, I would like to thank all staff at the KLB biological services unit for always doing their best to facilitate my animal work and safeguard the welfare of the mice I was privileged to use for my research. Thanks to all my beloved family and friends for their support. Thanks to my aunt Ellen McVey, uncle Kevin Murphy and my friends Dr Louise China, Jonathan Johnson and Emma McFadden for letting me stay with them when I needed to undertake my final experiments. Special thanks to my graduate tutor Dr David Sattelle and my friend Dr Benjamin Bennett for their feedback, advice and guidance with regard to the resubmitted version of this thesis. Finally, I would like to thank the MBPhD programme for giving me the opportunity and funding to study for a PhD, it has been an incredible privilege. 6 Explanation of Acronyms and Abbreviations 2-ME 2-Mercaptoethanol AIM2 Absent in Melanoma 2 AP-1 Activator Protein 1 APRIL A Proliferation Inducing Ligand BAFF B cell Activating Factor BCA Bicinchoninic Acid BCG Bacillus Calmette-Guerin BCR B Cell Receptor BSA Bovine Serum Albumin CD11b-ve CD11b-Negative Cells cDC Conventional Dendritic Cell. Type 1 = cDC1, type 2 = cDC2 cDNA Complementary DNA CFA Complete Freund’s Adjuvant CFU Colony Forming Unit CLEC2 C-type Lectin-like receptor 2 CNS Conserved Non-coding Sequence Con Contralateral Contra Contralateral COX Cyclooxygenase CpG C-phosphate-G Nucleotides CREB cAMP Response Element Binding Protein Ct Cycle Threshold CTRL Control – refers to either (1) the ipsilateral superficial parotid lymph nodes of mice injected with appropriate control diluent, (2) the collective term to refer to contralateral, inguinal and control lymph nodes or (3) cell suspensions not exposed to inflammatory stimuli in vitro. Please see figure legends. DAB Diaminobenzidine 7 DC Dendritic Cell dLN Draining Lymph Node DMSO Dimethyl Sulphoxide DNA Deoxyribonucleic Acid dNTP Deoxyribonucleotide Triphosphates EDTA Ethylenediaminetetraacetic acid EGR Early Growth Response Transcription Factors ELISA Enzyme-Linked Immunosorbent Assay ELISPOT Enzyme-Linked Immunospot FACS Fluorescence-Activated Cell Sorting FBS Fetal Bovine Serum FDC Follicular Dendritic Cell FLICA Fluorochrome-Labelled Inhibitor of Caspase 1 FMO Fluorescence Minus One Control FRC Fibroblastic Reticular Cell FSC-A Forward Scatter Area GC Germinal
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