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Title: Role of MIZ1/MYC interaction in germinal centre B cells
Author: Toboso Navasa, María Amparo
ISNI:       0000 0004 7659 938X
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Affinity-matured memory B cells (MBCs) and antibody-secreting plasma cells (PCs) produced during the germinal centre (GC) reaction are key for the long-term immunity against pathogens. The GC is a T cell-dependent B cell reaction that occurs upon antigen encounter. In GCs, B cells cyclically migrate between dark zone (DZ) and light zone (LZ). DZ cells undergo proliferation and somatic hypermutation of the B cell receptor (BCR) genes to increase affinity towards the antigen. BCR engagement and T cell help positively select LZ cells and induce the expression of the transcription factor MYC. MYC is critical to maintain the GC reaction, ensuring that LZ cells re-enter cell cycle and migrate back to the DZ. Another key transcription factor, BCL6, allows GC cells to tolerate DNA damage while proliferating and mutating their BCR. MYC activates gene expression but also functions as a repressor when interacting with the transcription factor MIZ1 (ZBTB17). MIZ1 is implicated in the response to stress and described to be a transcriptional activator of negative regulators of cell cycle. In GC-derived lymphoma cells, BCL6 binds MIZ1 and represses BCL2 and CDKN1A. Nevertheless, MIZ1 function in GC physiology is yet to be described, as is the role of its interaction with MYC and BCL6. Here, MIZ1 was found to be mainly expressed in MYC-positive LZ cells. MIZ1/MYC interaction was not essential for GC formation but critical for its maintenance. The function of MYC in the complex could not be replaced by BCL6. This function was required for the genetic programme of positively selected LZ cells, allowing them to cycle, specially the higher affinity ones. Moreover, the genetic programme imposed by MIZ1/MYC interaction counteracted the MBC differentiation programme since the abrogation of MIZ1/MYC complexes, apart from impacting GC size, increased the production of MBCs bearing lower affinity BCRs.
Supervisor: Calado, D. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available