Dphil student of clinical medicine
The threshold of B cell signalling in positive and negative selection by antigen
B2 cell is the most common type of B cell in immune system, always found in marginal zone or follicular zone in spleen, which can be renewed with precursor of adult bone marrow. High affinity antibodies can be generated when encountered foreign antigen with the help of T cell-depended affinity mutation and somatic hypermutation of BCR.
B1 cell, unlike B2 cell, shows several distinctive features: weak self-reactive, IgM dominant production, self-renewed and ability of secreting natural protective antibodies in absence of antigen(Baumgarth 2016, Vanhee, Åkerstrand et al. 2019).Although this type of early appeared B cell only makes up less than 5% of total B cell in blood and spleen(Baumgarth 2011), comparing with conventional B2 cell, B1 cell seems to be selected by a novel method, while the mechanism and molecular basis behind are still unknown.
During early ontogeny, interactions with intracellular or low abundance self-antigens allow positive selection of innate-like B1 B cells. In contrast, the presence of abundant soluble or low-avidity self-antigen leads to B-cell anergy, and stronger signals from highly abundant or multivalent antigens trigger receptor editing or deletion as part of the negative selection of immature B cells in central tolerance. Despite the importance of antigen quality and quantity in modulating B-cell responses, little is understood about the process that defines the signaling threshold between positive and negative selection, allowing B-cells to discriminate between antigens of varying strength and form.
The main objective of my Dphil project is looking for the key elements in B cell selection, especially B1 cell selection , with the help of transgenic mice models. We will first focus on the genes that alter the selection threshold of B1 cell in mice model. Once genes have been targeted, subsequent functional test and signal pathway test will be performed. In the mean time, different forms and avidity of self antigens will be used in these models to unveil the importance of antigen type in B cell selection.
Baumgarth, N. (2016). "B-1 Cell Heterogeneity and the Regulation of Natural and Antigen-Induced IgM Production." Front Immunol 7(324).
Vanhee, S. et al. Lin28b controls a neonatal to adult switch in B cell positive selection. Science Immunology 4, eaax4453 (2019).
Baumgarth, N. (2011). "The double life of a B-1 cell: self-reactivity selects for protective effector functions." Nature reviews. Immunology 11(1): 34-46.