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

	PDF Elizabeth Natkanski PhD Thesis.pdf Available under License : See the attached licence file. Download (40MB)
	AVI video (Supplement: Movie 1: B1 8 B cells on antigen) Movie_1_B1_8_B_cells_on_antigen_loaded_PLB.avi Download (2MB)
	AVI video (Supplement: Movie 2: B16 B cells on antigen) Movie_2_Bl6_B_cells_on_antigen_loaded_PMS.avi Download (12MB)
	AVI video (Supplement: Movie 3: Dil stained invaginations and antigen microclusters) Movie_3_DiI_stained_invaginations_and_antigen_microclusters.avi Download (4MB)
	AVI video (Supplement: Movie 4: B16 B cell expressing Clathrin light chain GFP on antigen loaded PMS) Movie_4_Bl6_B_cell_expressing_Clathrin_light_chain_GFP_on_antigen_loaded_PMS.avi Download (13MB)
	AVI video (Supplement: Movie 5: BL6 B cells expressing Myosin IIA RLC GFP on DiD stained antigen loaded PMS) Movie_5_BL6_B_cells_expressing_Myosin_IIA_RLC_GFP_on_DiD_stained_antigen_loaded_PMS.avi Download (3MB)
	AVI video (Supplement: Movie 6: B16 B cells expressing LifeAct on DiD stained Antigen loaded PMS) Movie_6_Bl6_B_cells_expressing_LifeAct_on_DiD_stained_Antigen_loaded_PMS.avi Download (5MB)

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.

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