The functional role of interferon regulatory factor 4 in plasma cells
AuthorLow, Michael Sze Yuan
Document TypePhD thesis
Access StatusOpen Access
© 2018 Dr. Michael Sze Yuan Low
Plasma cells are a critical component of the adaptive immune system being responsible for the production of large amounts of antibodies which can bind and remove pathogens. Plasma cell formation and function is regulated by the interactions between pro-plasma cell and pro-B cell transcription factors. Transcription factors which promote plasma cell fate include IRF4, Blimp-1 and XBP-1. In the absence of IRF4 plasma cells fail to differentiate from B cells and established plasma cells rapidly die. IRF4 is therefore known to be critical for plasma cell differentiation and survival, however, the mechanism by which it exerts its function remains unclear. The work in this thesis aims to define this mechanism. In this thesis, the deletion of IRF4 was identified to induce apoptosis in plasma cells. An in-vivo model was established which allowed the conditional deletion of IRF4 whilst over-expressing the anti-apoptotic protein Bcl-2 during which a proportion of plasma cells survived IRF4 deletion (Chapter 3). This in-vivo model allowed for a detailed interrogation into the transcriptional changes that occur on IRF4 deletion in plasma cells. RNA sequencing identified that IRF4 plays a critical role in plasma cell identity by transcriptionally regulating cell surface proteins such as CD138, transcription factors such as XBP-1 and immunoglobulin heavy and light chains (Chapter 4). Additionally, IRF4’s transcriptional network suppresses other lymphoid lineages, however, a loss of IRF4 does not cause plasma cells to de-differentiate into B cells (Chapter 4). A loss of IRF4 leads to structural changes in plasma cells predominantly manifesting as a reduction in the amount of endoplasmic reticulum; changes which are likely mediated by reduced XBP-1 protein levels. In addition, IRF4 plays a role in regulating plasma cell metabolism with deletion leading to increased metabolic capacity, mitochondrial numbers and increased reactive oxygen species (Chapter 5). In conclusion, this thesis defines the changes that occur within established plasma cells on IRF4 deletion and places IRF4 in a central and indispensable role for the cellular function and identity of plasma cells.
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- Medical Biology - Theses