Molecular mechanisms of B Lymphocyte differentiation and activation
Lead Research Organisation:
Babraham Institute
Department Name: Immunology
Abstract
Antibodies produced B cells are key mediators of immunity that protect us from pathogenic micro-organisms such as bacteria and viruses. The production of high affinity antibodies is central to immunity and the principle of vaccination. However, self-reactive antibodies are common in human autoimmune diseases. Therapies that deplete B cells are proving successful in common but crippling diseases such as Rheumatoid Arthritis. Cancers of B cell origin comprise the majority of lymphoid malignancies and many B cell malignancies remain incurable. Thus the study of B lymphocytes in health and disease is directly relevant to our attempts to improve vaccine design; to develop new treatments for autoimmune disease; and to develop therapies to combat B cell malignancies.
The objective of reducing morbidity and mortality associated with diseases where B cell play a role requires a fuller understanding of the molecular mechanisms that regulate B cell activation and differentiation. This project seeks to uncover mechanisms that control the development and function of B cells. The project proposes to test the hypothesis that the activity of key genes required for B cell differentiation are regulated by a novel mechanism acting on the messenger RNA. If correct, it will change the way we think about B cell differentiation.
The objective of reducing morbidity and mortality associated with diseases where B cell play a role requires a fuller understanding of the molecular mechanisms that regulate B cell activation and differentiation. This project seeks to uncover mechanisms that control the development and function of B cells. The project proposes to test the hypothesis that the activity of key genes required for B cell differentiation are regulated by a novel mechanism acting on the messenger RNA. If correct, it will change the way we think about B cell differentiation.
Technical Summary
B cells play key roles in both health and disease and further understanding of the molecular regulation of B cell differentiation is important for progress in vaccine design and for the development of therapies to treat autoimmunity and B cell malignancies.
The importance of a regulatory network of transcription factors controlling B cell identity, the germinal centre (GC) response and plasma cell differentiation is well established. However, important mechanistic gaps in our knowledge remain. In particular, the relative role of post-transcriptional control in the regulation of B cell differentiation remains unclear. We have limited knowledge of the signalling mechanisms that drive naïve B cells to become GC B cells and the signals that promote differentiation of GC B cells into the alternative cell fates of memory versus plasma cells. Post-transcriptional control could impart both speed and sensitivity to these processes. This project seeks to understand how B cell differentiation is regulated and to understand the importance of post-transcriptional control in that process.
A key hypothesis to be tested is that post-transcriptional mechanisms contribute to the process of B cell differentiation. Such mechanisms are increasingly being recognised as fundamental to most, if not all, biological processes including cell activation and differentiation. We have observed the rapid expression of genes that regulate mRNA stability and translation by B cells following BCR cross-linking and other stimuli and propose these promote the transition from naïve to GC B cell by extinguishing genes which determine the naïve B cell phenotype. We propose signals within the germinal centre, such as CD40, which promote the germinal centre phenotype do so, in part, by promoting the expression and function of post-transcriptional regulators. Post-transcriptional regulators expressed at high levels in the GC inhibit plasma cell differentiation by blocking expression of genes critical for the plasma cell phenotype. Signals emanating from the BCR, or other receptors, allow plasma cell differentiation by functionally inactivating post-transcriptional regulators. The role of post-transcriptional regulation, at the level of mRNA stability and translation, will be tested using genetic models in which genes can be specifically deleted in resting or activated B cells and B cell differentiation studied at the level of GC/plasma cell differentiation. The programme of work will identify the importance of these genes for B cell responses and provide mechanistic insights by identifying target genes that are regulated at the level of RNA stability and/or translation.
The importance of a regulatory network of transcription factors controlling B cell identity, the germinal centre (GC) response and plasma cell differentiation is well established. However, important mechanistic gaps in our knowledge remain. In particular, the relative role of post-transcriptional control in the regulation of B cell differentiation remains unclear. We have limited knowledge of the signalling mechanisms that drive naïve B cells to become GC B cells and the signals that promote differentiation of GC B cells into the alternative cell fates of memory versus plasma cells. Post-transcriptional control could impart both speed and sensitivity to these processes. This project seeks to understand how B cell differentiation is regulated and to understand the importance of post-transcriptional control in that process.
A key hypothesis to be tested is that post-transcriptional mechanisms contribute to the process of B cell differentiation. Such mechanisms are increasingly being recognised as fundamental to most, if not all, biological processes including cell activation and differentiation. We have observed the rapid expression of genes that regulate mRNA stability and translation by B cells following BCR cross-linking and other stimuli and propose these promote the transition from naïve to GC B cell by extinguishing genes which determine the naïve B cell phenotype. We propose signals within the germinal centre, such as CD40, which promote the germinal centre phenotype do so, in part, by promoting the expression and function of post-transcriptional regulators. Post-transcriptional regulators expressed at high levels in the GC inhibit plasma cell differentiation by blocking expression of genes critical for the plasma cell phenotype. Signals emanating from the BCR, or other receptors, allow plasma cell differentiation by functionally inactivating post-transcriptional regulators. The role of post-transcriptional regulation, at the level of mRNA stability and translation, will be tested using genetic models in which genes can be specifically deleted in resting or activated B cells and B cell differentiation studied at the level of GC/plasma cell differentiation. The programme of work will identify the importance of these genes for B cell responses and provide mechanistic insights by identifying target genes that are regulated at the level of RNA stability and/or translation.
