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Title: An investigation into the biology and function of protein Icb-1
Author: Cheng, Daian
ISNI:       0000 0004 2746 7444
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2013
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In this thesis I describe an investigation into the function of the protein Icb-1, a homologue of Themis1 in B cells and monocytes. Themis1 is important for T cell positive and negative selections. Yet its function in T cell development is not clear. Although it shows characteristics of an adaptor protein and involvement in TCR-induced signalling, the exact signalling defects in Themis1-/- T cells remain obscure. Icb-1 is similar to Themis1 in sequence, function and binding partners. It has been studied in human tumour and macrophage cell lines, leading to limited conclusions. Its role in B cells has never been published. Given the link with Themis1, it is of great interest to investigate the function of Icb-1. My study has been focused on the comparison between Icb-1 knockout mice with wild-type controls. I characterised the B cell development in Icb-1-/- mice, either naturally born or produced as mixed adult bone marrow chimeras reconstituted from WT and Icb-1-/- donor cells. I examined the possible compensation and redundancy of Themis1 and Icb-1, by characterising Thems1/Icb-1 double knockout mice. The Ig-HEL mouse models were used to examine the change in B cell repertoire due to negative and positive selections. The mice were challenged with SRBCs or NP-CGG to examine the germinal centre response to foreign antigen when Icb-1 is absent. In vitro stimulation of B cells with soluble and membrane-bound antigens was used to investigate early B cell responses in detail and to give insights into the defects found in in vivo challenges. Finally, I examined the BCR-induced phosphorylation of key signalling molecules and Ca2+ flux in splenic B cells. The study revealed largely normal B cell development with subtle selection impairments, but a partially defected B cell immune response to antigens in Icb-1-/- mice. The marginal zone B cell population was enlarged in the absence of Icb-1, while the positive selection of B1 B cells induced by intracellular self-antigen was impaired. The deficient mice showed a reduction in germinal centre B cell generation. The defects are associated with impaired BCR-induced cell signalling to low abundance and/or low avidity antigens. In particular, Ca2+ flux and Erk1/2 phosphorylation were clearly reduced under certain conditions. The results shine a light on the function of protein Icb-1, and also improve our knowledge of Themis1 and the Themis family. They provide a new avenue of investigation into the regulation of BCR signalling, especially in Ca2+ flux induction and Erk1/2 activation. They also provide insight into how differential signalling is controlled within cells during activation and differentiation in response to antigens that vary in terms of affinity, avidity and frequency.
Supervisor: Cornall, Richard Sponsor: Wellcome Trust ; Clarendon Fund
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Immunology ; B lymphocyte ; Icb-1 ; Themis2 ; Themis1 ; BCR signalling