Feest, C; (2013) Global inhibition, local activation: Compartmentalisation of receptors on B cells. Doctoral thesis , UCL (University College London).

Abstract

B cells are a group of lymphocytes that contribute to the adaptive immune response by producing highly specific antibodies against a pathogen. In vivo, B cells get activated when they recognise a specific antigen on the surface of presenting cells through their B cell receptor (BCR). Several layers of molecular regulation tightly control this membrane-proximal process: Positive and negative co-receptors are organised in a way that allows for both the maintenance of a steady-state and, importantly, the quick amplification of an activatory signal. Compartmentalisation of the plasma membrane is emerging as a key concept in regulating receptor signalling. The aim of this thesis is to investigate the functional role compartmentalization plays for receptors and coreceptors with novel imaging approaches. I explore the dynamics and distribution of both isotypes of BCR, IgD and IgM, and of their main positive and negative co-receptors, CD19 and CD22. First, imaging techniques are implemented to achieve better time-resolution and higher spatial resolution. Using these super-resolution microscopy approaches, it is demonstrated that endogenous IgM, IgD, CD19 and CD22 exhibit similar non-random nano-scale organization and distinct dynamics within the plasma membrane of naïve B cells. Surprisingly, their global distribution is not dramatically altered during early BCR signaling, but nanoclusters of BCR and the positive co-receptor CD19 converge locally upon stimulation. The positive regulator CD19 is found to be largely immobile and is held in place by a member of the tetraspanin network, CD81. In contrast, the negative co-receptor CD22 is very mobile in the plasma membrane and regulated by its ability to bind to glycosilated proteins, foremost CD45. These findings lead to a model in which B cell activation is driven by a local disruption of the cytoskeleton that frees BCR for interaction with the positive co-receptor and allows the sequestering of the negative coreceptor.

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