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Development and Maturation of B cell Mediated Immune Responses


Weatherall Institute of Molecular Medicine

Friday, January 08, 2021 Competition Funded PhD Project (UK Students Only)

About the Project

We study the cellular interactions and molecular events that lead to the development of high affinity and protective antibodies during humoral immune responses. Our main focus is the germinal centre reaction.

The development of pathogen-specific antibodies is a principle mechanism by which adaptive immune responses clear ongoing infections and protect against re-infection. The quality of the antibodies made improves over the course of immune responses as a result of a remarkable process known as antibody affinity maturation. Antibody affinity maturation occurs within germinal centres, organised structures that form in the B cell follicles of local secondary lymphoid tissues such as lymph nodes and the spleen. Germinal centre B cells “evolve” their antibody genes through iterative rounds of antibody gene mutagenesis (somatic hypermutation) and affinity-based selection. The somatic hypermutation process targets antibody genes in a largely random manner, therefore selection involves screening out cells where the process has been harmful to antibody function and preferentially expanding B cells whose antibodies have been improved. Germinal centres are remarkably dynamic structures in which with B cells move back and forth between these periods of antibody gene somatic hypermutation and selection approximately once per day, which poses unique cell biology challenges. Despite the fundamental importance of germinal centres to acquired immunity, the events and processes controlling them are far from fully understood. This is especially true in the context of complex infections such as HIV and malaria; some of the specific challenges posed in these setting are discussed in Bannard and Cyster, Curr. Opin. Immunol. 2017 (PMID: 28088708). The quest of our lab is to fill some of these knowledge gaps. We hope that the advances we make will help inform the development of new or improved vaccine approaches.

Projects in the Bannard laboratory focus on trying to understand the cellular interactions and regulatory mechanisms that facilitate antibody affinity maturation. We aim to understand what “selection” entails, and we hope to determine how germinal centre B cells make fate choices such as when to switch between specific states or differentiate. We also are interested in employing our knowledge of “normal” antibody responses to better understand why immunity is slow to develop during malaria infections; therefore, projects are also available in this area. In addition, we want also understand how B cell responses might be better harnessed for developing effective vaccines. To reach these goals, we employ a wide range of cutting-edge techniques such as high-end flow cytometry, confocal microscopy, live cell imaging (e.g. multi-photon), single B cell cloning and next generation sequencing. Our work relies heavily on sophisticated genetically modified in vivo systems and we often use live virus infections (e.g. Influenza A). As such, students can expect to receive sound intellectual and practical science training.

Informal enquiries are welcomed and can be directed to . >

Project will be based in the Bannard lab in the Weatherall Institute of Molecular Medicine (WIMM). This is a small group and so students will benefit from frequent interactions with their supervisor.

Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division’s Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.




Funding Notes

Funding for this project is available to scientists through the WIMM Prize Studentship, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

For October 2021 entry, the application deadline is 8th January 2021 at 12 noon midday, UK time.

Please visit our website for more information on how to apply.

References

1 Stewart, I., Radtke, D., Phillips, B., McGowan, S. J., & Bannard, O. (2018). Germinal Center B Cells Replace Their Antigen Receptors in Dark Zones and Fail Light Zone Entry when Immunoglobulin Gene Mutations are Damaging. Immunity, 49(3), 477–489.e7.

2 Radtke, D., & Bannard, O. (2018). Expression of the Plasma Cell Transcriptional Regulator Blimp-1 by Dark Zone Germinal Center B Cells During Periods of Proliferation. Frontiers in Immunology, 9, 3106.
3 Bannard, O., and Cyster, J.G. (2017). Germinal centers: programmed for affinity maturation and antibody diversification. Curr. Opin. Immunol. 45, 21–30.

4 Bannard, O., McGowan, S.J., Ersching, J., Ishido, S., Victora, G.D., Shin, J.-S., and Cyster, J.G. (2016). Ubiquitin-mediated fluctuations in MHC class II facilitate efficient germinal center B cell responses. J. Exp. Med. 213, 993–1009.

5 Bannard, O., Horton, R.M., Allen, C.D.C., An, J., Nagasawa, T., and Cyster, J.G. (2013). Germinal center centroblasts transition to a centrocyte phenotype according to a timed program and depend on the dark zone for effective selection. Immunity 39, 912–924.

6 Bannard, O., Kraman, M., Fearon, D.T. (2009). Secondary replicative function of CD8+ T cells that had developed an effector phenotype. Science, 323(5913):505-509.

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