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Title: Not-so-innocent bystanders? : investigating non-antigen specific CD8+ T cell activation in autoimmune prognosis
Author: Pecchia-Bekkum, Annika Gabriel
ISNI:       0000 0004 7968 3624
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Clinical outcome in patients with the same diagnosis of immune disease varies substantially. Understanding the biology of prognosis could greatly improve treatment options for patients suffering from more severe forms and reduce treatment-related side effects for those on a milder disease course. Previously, the Smith Laboratory identified a novel gene expression signature in T cells predictive of clinical outcome in anti-neutrophil cytoplasmic antibodies-associated vasculitis, systemic lupus erythematosus, Crohn's disease, and ulcerative colitis that is not associated with diagnosis. Two modules (corresponding to sets of co-correlated genes) contained within the CD4+ and CD8+ T cell populations correlated with prognosis: a milder disease course is associated with a characteristic transcriptional signature of CD8+ T cell exhaustion (defined as the progressive loss of effector function in the presence of persistent antigen) and poor outcome associated with CD4+ T cell co-stimulation. Preliminary work by Smith laboratory members (McKinney and Kent) shows that genes associated with bystander activation (BA), the non-TCR-specific activation of T cells were enriched in patients with relapsing disease. Therefore, non-antigen-specific ("bystander") cells may be playing an important role in prognosis. I sought to address the mechanism underlying BA and gain greater insight into its mechanism of action and possible ways to modulate a BA response. I investigated the transcriptomes and phenotypes of BA cells within two model systems. Using these systems, I explored to what degree the 1) identity of the bystander, 2) identity of the TCR-activated cell, and 3) chosen stimulus affected a bystander response. These data demonstrated that BA response are heterogeneous, occur primarily in memory phenotype cells, and involve cytokine-cytokine receptor signalling. Most importantly, these BA cells appear phenotypically and transcriptionally similar to TA cells and may reflect the manner in which TCR-activation occurs, thus suggesting why the prognostic signature is observed in bulk CD8+ T cells. An in vivo human vaccination experiment generated an analogous, but non-identical BA signature. Enrichment of these condition-specific transcriptomes within disease cohorts led to the identification of possible models of disease for downstream analysis. My thesis demonstrated that BA is a complex and context-dependent phenomenon relevant to disease prognosis.
Supervisor: Smith, Ken Sponsor: Gates Cambridge Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: CD8+ T cells ; Autoimmune disease ; T cell exhaustion ; Bystander activation ; Prognosis