Understanding the mechanisms of immune receptor signalling and how to target this process in disease

B lymphocytes play a crucial role in adaptive immunity, being responsible for antibody production as well as contributing to antigen presentation and cytokine secretion to coordinate the immune response. Stimulation of B cells occurs primarily through the B-cell receptor (BCR), a surface-exposed membrane-integrated immunoglobulin. Antigen binding to the BCR stimulates a number of downstream signalling pathways that control B-cell differentiation, proliferation and migration. Dysregulation of BCR signalling is responsible for human malignancies such as lymphoid leukaemia and lymphoma and is also associated with various immunological disorders. Because of its crucial importance in B cell physiology, the BCR has been intensively investigated for many years. In our recent work, we have uncovered a novel mechanism controlling BCR clustering and signalling, which involves the inositol phosphatase INPP5B. Preliminary results also suggest INPP5B is important for B cell physiology and the proliferation of lymphoma cells. The goal of this project is to build upon our work to date to decipher the molecular details of how INPP5B controls BCR dynamics, how this occurs in time and space, and to determine its significance for normal B cell functions as well as those occurring in cancerous B cells. The project will involve cell biology and immunological techniques, which will include proteomics, high-end live and fixed cell imaging, combined with immune phenotyping, cancer cell proliferation and migration assays. The findings will provide major new insights into the BCR and will have significant implications for our understanding of the healthy immune system, as well as B cell disorders such as leukaemia and lymphoma.