Grant: Project Grant

Production of high affinity antibodies after virus such as COVID-19 infections or vaccination is the linchpin of the protective immunity. However, the molecular mechanism regulating high affinity antibody production is not fully understood. High affinity antibodies are produced in the germinal center (GC) in which antigen-specific B cells modify and select their antibody encoding genes in order to become high affinity antibody producing plasma cells (PCs). Abnormal regulation of molecules in B cells may lead to immune deficiency, autoimmune diseases, and even B lymphomas. In this regard, it is important to elucidate B cell intrinsic mechanisms that control the GC reaction under physiological and pathological conditions. In our previous CIHR supported studies, we have demonstrated that CBL and CBL-B (CBLs)-mediated ubiquitination plays a critical role in high affinity antibody production. CBLs do so by enabling B cells to get help from T cells and controlling GC B cells to differentiate into PCs only after they acquired a high affinity antibody. Our recent experiments further reveal that CBLs themselves are temporally regulated at different stages of the GC reaction and may involve the degradation of CBLs by the lysosomes regulated by TFEB, a master regulator for lysosome biogenesis. Interestingly, removal of CBLs from B cells leads to development of B cell lymphomas, indicating that CBLs are tumor suppressors preventing B lymphomas. Here, we propose to explore molecular mechanisms how GC B cells temporally control the expression of CBLs during the dynamic GC reaction. In addition, we will explore the role of TFEB in generating high affinity antibody producing PCs. Moreover, we will elucidate how CBLs prevent B lymphomagenesis and whether they also contribute to human B lymphomas. Completion of this project will not only bring new insight into our understanding of the antibody production but also help to treat various immune system disorders and cancer.