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Investigating Novel Components and Mechanisms Involved in B Cell Receptor-Antigen Internalisation

Natkanski, EM; (2013) Investigating Novel Components and Mechanisms Involved in B Cell Receptor-Antigen Internalisation. Doctoral thesis , UCL (University College London). Green open access

[thumbnail of Elizabeth Natkanski PhD Thesis.pdf] PDF
Elizabeth Natkanski PhD Thesis.pdf
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[thumbnail of Supplement: Movie 1: B1 8 B cells on antigen] AVI video (Supplement: Movie 1: B1 8 B cells on antigen)
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[thumbnail of Supplement: Movie 3: Dil stained invaginations and antigen microclusters] AVI video (Supplement: Movie 3: Dil stained invaginations and antigen microclusters)
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[thumbnail of Supplement: Movie 4: B16 B cell expressing Clathrin light chain GFP on antigen loaded PMS] AVI video (Supplement: Movie 4: B16 B cell expressing Clathrin light chain GFP on antigen loaded PMS)
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[thumbnail of Supplement: Movie 5: BL6 B cells expressing Myosin IIA RLC GFP on DiD stained antigen loaded PMS] AVI video (Supplement: Movie 5: BL6 B cells expressing Myosin IIA RLC GFP on DiD stained antigen loaded PMS)
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[thumbnail of Supplement: Movie 6: B16 B cells expressing LifeAct on DiD stained Antigen loaded PMS] AVI video (Supplement: Movie 6: B16 B cells expressing LifeAct on DiD stained Antigen loaded PMS)
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Abstract

The elimination of a wide variety of infections requires the production of high affinity antibodies specific for the invading pathogen. The generation of these high affinity antibodies depends on the ability of B cells to recognise and internalise antigens from the surface of antigen-presenting cells (APCs) in an affinity-dependent manner. B cells expressing high affinity B cell receptors (BCRs) internalise, process and present more antigen, obtain better T cell help, and are selectively expanded over lower affinity equivalents. However, the molecular mechanisms by which B cells extract antigens for presentation remain unclear. Using a new fluid and flexible membrane substrate to mimic APCs, we show that B cells acquire antigen by dynamic myosin IIA-mediated contractions that pull out and invaginate the presenting membranes. Invaginations containing high affinity BCR-antigen microclusters were able to withstand the force of these contractions and recruit clathrin resulting in endocytosis. In contrast, low affinity BCR-antigen bonds quickly ruptured aborting internalisation. Thus we conclude that coupling contractility to endocytosis permits B cells to discriminate between antigen affinities, which provides a mechanism for the selective advantage seen for high affinity B cell clones in vivo. Disruptions in BCR-antigen internalisation has been linked to the growth of malignant B cells and the development of autoimmunity. Therefore, ultimately, our results could contribute to the effective design of future therapeutics for B cell diseases.

Type: Thesis (Doctoral)
Title: Investigating Novel Components and Mechanisms Involved in B Cell Receptor-Antigen Internalisation
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: B cell receptor
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/1413024
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