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Dissecting immune interactions in health and disease with multiomics and spatial technologies https://doi.org/10.17863/CAM.106984 Arutyunyan, Anna Vento-Tormo, Roser Cells are the basic building blocks of life, forming the enormous plethora of tissues and living organisms on Earth. They have a high diversity of phenotypes and functions in different environments. The high-throughput tools to profile different modalities from a single cell have grown exponentially in recent years. This now allows us to draw a complete picture of how cells function in different environments for the first time. In the work of my thesis, I use high-throughput multiomics and spatial technologies to create comprehensive cell atlases. I focus on studying the immune cell communication among themselves and with other cells in the context of disease and development. Chapter 1 starts with an outline of the background on cell biology and the impact that genomic technologies have on how we can study cellular processes. I then discuss the experimental methodology of high-throughput multiomics and spatial techniques, and computational tools for the analysis of such data. Following is the introduction to the two projects comprising the work of my thesis: (i) a multiomics study of Common Variable Immunodeficiency (CVID) and, (ii) a spatial multiomics map of the Maternal-Fetal Interface (MFI) in early pregnancy in humans. Chapter 2 outlines materials and methods used in this work, showcasing the workflow for each project. Chapter 3 details the multiomics atlas of Common Variable Immunodeficiency (CVID). This condition is characterised by defects in the function of B cells, a type of adaptive immune cells capable of producing antibodies to fight infections. I analyse gene expression and chromatin accessibility data of B cells from a pair of monozygotic CVID-discordant twins. I uncover potential defects in the epigenome of the affected twin’s B cells. Next, after in vitro stimulation of these twins’ PBMCs, I observe CVID-associated transcriptional dysregulation in immune subsets additional to those in B cells. I discover defects in the immune cell crosstalk between B cells and other immune compartments of the CVID twin. With an expanded cohort of CVID patients and healthy individuals, I go on to further validate these findings. These results show that, in addition to B-cell-intrinsic alterations, defects in cell-cell communication between B cells and other immune compartments may be compromising the correct immune response in CVID. Chapter 4 presents the work on creating a comprehensive spatial multiomics atlas of the maternal-fetal interface in early pregnancy. Firstly, I characterise the signatures and differentiation trajectories of trophoblast cells - the building blocks of placenta. I then focus on the crosstalk between invading trophoblast and maternal immune cells. I predict putative cell-cell communication events and validate in situ the selected molecules mediating these interactions. I propose a model of arterial transformation facilitated by fetal trophoblast and their communication with maternal cells. This work expands our knowledge about the cellular and molecular players in the maternal-fetal dialog in the first trimester of pregnancy, definitive of its success. Chapter 5 describes the work on modelling the dialog between decidual natural killer (dNK) cells, a type of innate immune cell most abundant in pregnant decidua, and the invading trophoblast at the maternal-fetal interface using primary trophoblast organoids (PTO). I benchmark the PTO system against the in vivo trophoblast atlas I described in chapter 4. After defining trophoblast cell states in vitro, I perform comparative analysis of PTOs stimulated with a cocktail of chemokines that in vivo are secreted by dNK cells and unstimulated PTOs as control. I propose a putative effect of the signals from dNK cells on trophoblast invasion in the first trimester of pregnancy. Lastly, Chapter 6 provides an overview of all the described work, as well as a discussion of how the novel high-throughput multiomic and spatial technologies together with in vitro models shape our current view of fundamental biology, and how they will impact future directions of research. University of Cambridge 2023-09-01 Thesis Doctoral Doctor of Philosophy (PhD) eng Wellcome Trust 4-Year PhD Studentship https://www.repository.cam.ac.uk/handle/1810/365923 https://www.repository.cam.ac.uk/bitstreams/061771b9-3ef9-4882-8b15-6fea9c7c9af7/download 20efb2dc3977b42078be1a6507fb8058 https://www.repository.cam.ac.uk/bitstreams/1a2f169f-d642-4cff-8bce-a85981250c3e/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ Cell-cell communication CVID Maternal-fetal interface Single-cell genomics