Castello, A; (2013) Regulatory Mechanisms of Antigen Encounter and BCR Signalling. Doctoral thesis , UCL (University College London).

Abstract

Activation of B cells is dependent on two events: the encounter of cognate antigen and the triggering of an adequate B cell receptor (BCR) signal. In vivo B cells encounter antigen within secondary lymphoid organs, such as lymph nodes (LNs). Here, specialised CD169+ macrophages, strategically located across the fenestration of the inner wall of the subcapsular sinus (SCS), trap lymph-borne antigen and present it to B cells. I have shown that within CpG-inflamed LNs, CD169+ macrophages undergo a dramatic reorganisation by retracting from the inner wall fenestration and scattering along the edges of the tissue. These events are partly caused by the arrival of dendritic cells pushing away the macrophages form the SCS fenestration to gain access to the LN. In vitro CD169+ macrophages were found to respond directly to CpG by downregulating CD169 and some scavenger receptors, while upregulating the expression of interferon-γ. Because of these structural and phenotypic changes, antigen retention at the SCS is impaired resulting in fewer B cells encountering their cognate antigen and weaker antibody responses. Antigen encounter is important because it initiates BCR signalling. Within a signalling cascade, adaptor proteins act as signal integrators and amplifiers. The adaptor protein Nck is best known for linking receptor signalling to cytoskeleton regulation. However upon B cell activation I found that Nck controls the PI3K/Akt pathway by recruiting the B-cell adaptor for PI3K (BCAP). Nck can carry out these functions by directly binding to the BCR via the non-ITAM phospho-tyrosine 204 in the Igα tail. Importantly, genetic ablation of Nck resulted in defective BCR signalling leading to hampered survival and proliferation in vivo. Antibody responses in Nck-deficient animals were thus severely impaired. Collectively these findings are important as they shed light on some of the regulatory mechanisms for antigen encounter and BCR signalling.

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