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Development and Maturation of B cell Mediated Immune Responses

  • Full or part time
  • Application Deadline
    Friday, January 10, 2020
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

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 quality of antibodies improves over the course of immune responses due to antibody affinity maturation. This remarkable process occurs within specialised structures, known as germinal centres, that form within B cell follicles of the local secondary lymphoid tissues. Here, B cells “evolve” their antibody genes through the random introduction of somatic mutations, and by selection. Cells with damaging mutations are screened out, while cells carrying nucleotide changes that enhance antibody:antigen binding are preferentially expanded. Despite its fundamental importance in acquired immunity, the events involved in this selection process remain incompletely understood. This is especially true in the context of “real” infections, where antigens are often complex. Most pathogens display a plethora of epitopes and the best neutralization sites are commonly “challenging” targets. For example, broadly neutralising antibodies against HIV develop in germinal centres, but only infrequently, and only after months or years of acquiring mutations. These problems are discussed in more depth in Bannard and Cyster, Curr. Opin. Immunol. 2017 (PMID: 28088708).

Projects in the Bannard laboratory focus around trying to decipher the fundamental biology underpinning the development of humoral immunity. We investigate the cellular interactions and regulatory mechanisms that facilitate antibody affinity maturation. We aim to understand what “selection” entails, and we hope to determine how cells make fate choices such as when to 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. 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.

This is a small group and so students will benefit from frequent interactions with their supervisor.

Informal enquiries are welcomed and can be directed to .

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 RDM Scholars Programme, 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 2020 entry, the application deadline is 10th January 2020 at 12 noon (midday).
Please visit our website for more information on how to apply.

References

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.

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.
Bannard, O., and Cyster, J.G. (2017). Germinal centers: programmed for affinity maturation and antibody diversification. Curr. Opin. Immunol. 45, 21–30.

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.

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.

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.

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

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