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Signalling and transcriptional pathways regulating memory B cell formation, persistence and function

  • Full or part time
    Dr V Tybulewicz
  • Application Deadline
    Tuesday, November 12, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

This 4-year PhD studentship is offered in Dr Victor Tybulewicz’s Group based at the Francis Crick Institute (the Crick).

Immunological memory is a hallmark of the mammalian adaptive immune response, resulting in improved protection to re-infection by a pathogen. Memory B cells (MBC) are long-lived cells that are generated during a primary immune response and provide a repository of B cells expressing B cell antigen receptors (BCRs) with specificity for the pathogen. They can be generated either directly following activation of naïve B cells or can arise in germinal centres where the B cells undergo multiple rounds of somatic hypermutation that increase the affinity of their BCRs for antigens derived from the pathogen. On subsequent re-infection, MBC are rapidly activated and recruited into germinal centres where they undergo further affinity maturation and differentiate into antibody-secreting plasma cells, thereby providing the enhanced immunity that characterises immunological memory.

Despite their importance, MBC have been poorly studied, in part because of a lack of methods to investigate this low abundance cell type. Thus, very little is known about the signalling and transcriptional pathways that control the development, persistence and function of MBC. Our group is currently generating a novel binary genetic system that will allow us to inactivate genes exclusively in MBC, a capability that is currently not available anywhere else. This will also allow us to follow the fate of MBC during the course of primary and secondary immune responses. In addition, we have generated extensive RNA sequencing (RNAseq) data on multiple subsets of B cells, including different MBC subtypes. From this data we have identified several transcription factors that are expressed preferentially in MBC compared to other B cell subsets.

The student will explore the function of these transcription factors using appropriate mouse genetic systems, for example inducibly inactivating the gene coding for a transcription factor of interest in MBC, and then studying the consequences of this on MBC survival and function. Furthermore, we think it is likely that MBC can develop along multiple trajectories. To analyse this, the student will extend our existing bulk RNAseq data with single cell RNAseq and ATACseq studies to identify the different developmental pathways that lead to MBC formation and re-activation, and use this to understand how the development of MBC is regulated.

The student is likely to use a range of techniques including mouse genetics, immunology, molecular biology, RNAseq or other genomic methods.

Candidate background
This project would suit candidates with a degree in biological or biomedical sciences or similar. The students should have an interest in immunology, genetics, cell biology or biochemistry. Candidates with skills in bioinformatics and/or coding are encouraged to apply.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2020 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.


Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.


1. Schweighoffer, E., Vanes, L., Nys, J., Cantrell, D., McCleary, S., Smithers, N. and Tybulewicz, Victor L. J. (2013)

The BAFF receptor transduces survival signals by co-opting the B cell receptor signaling pathway.

Immunity 38: 475-488. PubMed abstract

2. Ackermann, J. A., Nys, J., Schweighoffer, E., McCleary, S., Smithers, N. and Tybulewicz, V. L. J. (2015)

Syk tyrosine kinase is critical for B cell antibody responses and memory B cell survival.

Journal of Immunology 194: 4650-4656. PubMed abstract

3. Köchl, R., Thelen, F., Vanes, L., Brazão, T. F., Fountain, K., Xie, J., . . . Tybulewicz, V. L. J. (2016)

WNK1 kinase balances T cell adhesion versus migration in vivo.

Nature Immunology 17: 1075-1083. PubMed abstract

4. Schweighoffer, E., Nys, J., Vanes, L., Smithers, N. and Tybulewicz, V. L. J. (2017)

TLR4 signals in B lymphocytes are transduced via the B cell antigen receptor and SYK.

Journal of Experimental Medicine 214: 1269-1280. PubMed abstract

5. Schweighoffer, E. and Tybulewicz, V. L. J. (2018)

Signalling for B cell survival.

Current Opinion in Cell Biology 51: 8-14. PubMed abstract

Related Subjects

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