The role of the BAFF receptor in B cell survival

• Main Author: Fountain, Kathryn
• Format: Dissertation
• Language: English
• Published: UCL (University College London) 2017

Signalling through the BAFF receptor (BAFFR) is critical for the development and survival of B cells. The binding of BAFF to BAFFR leads to the recruitment and subsequent degradation of TRAF3, which results in the accumulation of NIK and induction of signalling through the non-canonical NFκB pathway. However, recent studies have shown that IKK1, a component of the alternative NFκB pathway, is required for B cell development, but not B cell survival. Concurrently, a number of other signalling molecules were shown to be of importance of B cell survival, including SYK, PI3K and the classical NFκB pathway. However, the mechanisms through which BAFFR transduces signals to these pathways remains unclear. The experiments described in this thesis sought to further understand the role of the BAFFR in controlling B cell survival. I have used inducible deletions to delete BAFFR and TRAF3 in mature B cells to determine their role in B cell survival. I have shown that TRAF3 deletion is only partially able to rescue B cell survival in BAFFR-deficient B cells, suggesting that there are additional interactors of BAFFR that transduce survival signals. To further understand how BAFFR transduces survival signals, I sought to identify novel proteins that interact with BAFFR. I generated a modified tandem affinity purification (moTAP)-BAFF, a tagged version of BAFF that can be used to stimulate and affinity purify BAFFR. Preliminary experiments have shown that, as expected, TRAF3 is one of the most enriched proteins in the BAFFR interactome. BAFF stimulation also leads to the recruitment of CD19 to BAFFR. It is hoped that further analysis of the BAFFR interactome will give insight into the receptor proximal events that control B cell survival. Finally, I developed a B cells survival assay to screen a panel of kinase inhibitors in order to identify novel kinases that are involved in B cell survival.