Plasma cells (PC) secreting high-affinity antibodies are key for long-term immunity and the success of vaccines. PC are mainly generated within the germinal centre (GC), a microenvironment where B cells undergo affinity maturation and selection. The GC reaction guarantees that only B cells expressing immunoglobulin with the highest affinity for the antigen will commit to terminal differentiation. Stringent regulation is essential, as dysfunctional GC B cells can cause defective immunity, autoimmunity, or B-cell lymphomas.
Affinity maturation requires rapid changes in the B cell transcriptome and proteome to enable cell fate decisions. This is governed by the interplay of signal transduction pathways and regulation at transcriptional and post-transcriptional levels. Post-transcriptional control is key for rapid remodelling of gene expression, yet its role in terminal differentiation remains largely unexplored. The host lab pioneers the study of RNA-binding proteins (RBP) in lymphocyte development and has unpublished data indicating that the RBP ZFP36L1 inhibits terminal differentiation of B cells in vitro. The regulation and function of ZFP36L1 in GCs is however unknown.
In this proposal I will build on the unique and multidisciplinary expertise of the host lab and my experience on post-transcriptional regulation and immunity to address how ZFP36L1 dictates fate decision of B cells. Uniquely available mouse models will allow me to study how signal strength and signal transduction control ZFP36L1 activity and its downstream implications for humoral immunity. Cutting-edge technologies will be employed to elucidate the dynamics of ZFP36L1-RNA interactions and how they in turn define the proteome and fate of GC B cells.
This work will reveal the role of an important new regulator of PC differentiation, and will enable me to expand my knowledge, acquire new biochemical, bioinformatics and managerial skills, and facilitate my career development as an independent scientist.
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