Verheijen, Melissa; (2019) Probing The Age Structure Within Population Of B-lymphocytes And Investigating The Impact Upon Their Life Long Maintenance. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Lymphocytes are continuously generated and destroyed throughout life, yet it is not understood how these life/death decisions are made and how they influence immune function. We examined B cell turnover throughout life using a chimeric mouse system that involves the treatment of host mice with conditioning drug busulfan. This specifically depletes hematopoeitic stem cells, leaving mature lymphocyte compartments intact. Following reconstitution with congenically labelled bone marrow, the progeny of new hematopoietic stem cells can be tracked for more than a year. Using this approach, we were able to analyse the tonic reconstitution of B cell compartments. Interestingly, we found that the naive B cell compartment is fully replaced in a relatively short time window, regardless of host age, suggesting that the B cell compartment is both homeostatically homogeneous and highly reliant on de novo generation of B cells for its long-term maintenance. Further investigation revealed extremely dynamic behaviour within different compartments, established by their age structure. In order to further understand the cellular mechanisms responsible for these dynamics, we considered different models for B cell homeostasis using mathematical modelling. This analysis confirms that follicular mature B cells behave homogeneously. All cells are lost at a fixed rate throughout life with a short lifetime. However, this life expectancy increases with host age. Similarly, germinal center B cells behave homogeneously. Although these cells persist three times longer in lymph nodes than in the spleen, modelling suggests that an extensive part of the compartment is replaced every day. Furthermore, we found the marginal zone B cells to behave homogeneously and that their lifespan is independent of host age. Whereas cell-proliferation was not important for marginal zone B cell maintenance at steady state, analysis of reporter mouse models suggests proliferating cells to be precursors of the marginal zone B cell compartment.

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