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    Investigating the role of TCR signalling during T cell development 
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    Investigating the role of TCR signalling during T cell development

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    Grandjean_Capucine_PhD_Final_231115.pdf (77.28Mb)
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    Queen Mary University of London
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    Abstract
    The thymus generates multiple T cell populations from an early common CD4(-) CD8(-) double negative (DN) progenitor. Conventional αβ T cells, such as CD4(+) and CD8(+) T cells undergo thymic positive selection on partial agonist interactions with self-peptide/MHC, whereas unconventional TCRαβ(+)CD8αα(+) intraepithelial lymphocytes (IELs) and regulatory T cells (Tregs), are thought to require full agonist interactions. By contrast, very little is known about how γδ T cells undergo selection. While it has been suggested that IL-17A-secreting γδ T cells rely on strong TCR signals resulting from potential interactions with a ligand, several studies have led to opposite conclusions. This thesis investigates the role of TCR signal strength during the early stages of thymocyte development, and how this dictates subsequent T cell fate. We show that FVB/n mice have relatively few unconventional TCRαβ(+)CD8αα(+) IELs in comparison to C57Bl/6 animals. This depleted IEL compartment correlated with reduced thymic IEL progenitors, an inefficient preTCR-driven DN-to-DP transition, and a relatively increased expression of full length pTαa transcripts in CD44(-)CD25(+) DN3 cells. Transgenic over-expression of pTαa in the absence of pTαb transcripts mimicked the phenotype of FVB/n animals. CD5 levels on DN3 cells from pTαa transgenic mice indicate that preTCR signalling was weaker than in C57Bl/6 mice, suggesting that signal strength at the β-selection checkpoint may influence subsequent selection of mature T cell populations. Consistent with this, we show that OT-II mice, which express a transgenic TCRαβ from an early DN stage of thymocyte 6 development, and which have high levels of CD5 on DN3 cells, have a relatively increased unconventional TCRαβ(+)CD8αα(+)IEL compartment. For γδ T cell development, we also show that weakening signal strength impairs the development of IL-17A-secreting γδ T cells. However, increasing signal strength, through the use of a cross-linking antibody, does not favour their development as predicted. These seemingly paradoxical observations are explored further. Taken together, these data suggest that the quality or quantity of TCR-mediated signals early in T cell development have fundamental consequences for subsequent T cell selection events that differentially generate distinct T cell subsets.
    Authors
    Grandjean, Capucine L-A
    URI
    http://qmro.qmul.ac.uk/xmlui/handle/123456789/12819
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    • Theses [3348]
    Copyright statements
    The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author
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