Tkacz, Claire; (2019) Computational analysis of innate and adaptive immune responses. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Both innate and adaptive immune processes rely on the activation of differentiated haematopoietic stem cell lineages to affect an appropriate response to pathogens. This thesis employs a largely network biology focused approach to better understand the specificity of immune cell responses in two distinct cases of pathogenic challenge. In the context of adaptive immunity, I studied the transcriptional responses of T cells during Graft-versus-Host Disease (GvHD). GvHD represents one of the major complications to arise following allogeneic hematopoietic stem cell transplantation and yet why only particular organs are damaged as a result of this pathology is still unclear. To investigate whether key GvHD transcriptional signatures seen in effector CD8+ T cells compared to naïve T cells are triggered in target organs or the secondary lymphoid organs, a module-based association test was developed to combine the output of gene clustering algorithms with that of differential expression analysis. This methodology significantly aided the identification of skin specific effector T cell transcriptional programs believed to drive murine GvHD pathogenesis at this site. Turning to the innate immune response, I investigated the transcriptional profiles of resting and activated macrophages in the setting of Tuberculosis (TB), the second leading cause of death from infectious disease worldwide. Regression-based analyses and clustering of macrophage expression data provided insight into the variations in gene expression profiles of naïve macrophages compared to those infected with Mycobacterium tuberculosis (MTB) or a vaccine strain of mycobacteria (BCG). The availability of genotype data as part of the macrophage dataset facilitated an expression quantitative trait loci (eQTL) study which highlighted a novel association between the cytoskeleton gene BCAR1 and TB risk, together with a previously undescribed trans-eQTL module specific to MTB infected macrophages. Potential genetic variants impacting expression of the aforementioned GvHD specific T cell transcriptional signatures were additionally investigated using external trans-eQTL datasets.

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