Characterisation of B cell gene signatures associated with greater affinity maturation

Background: Vaccination is one of the most impactful public health interventions to date beyond the provison of clean water, highlighted by the recent success of Covid19 vaccines. However, some highly variable pathogens continue to pose a major challenge for vaccinologists. In part this is because there remain many unanswered fundamental questions about how antibodies are generated and how this process can be manipulated for improved vaccination outcomes and the development of therapeutic antibodies.

It is well-established that antibodies are produced when B cells encounter their cognate antigen and become activated. Following this, the B cell can progresses through distinct differentiation states (plasmablast, memory B cell, plasma cell) and produce antibody into the blood to protect from infection. Immunological dogma suggests these changes in cellular phenotype are linked to the affinity of the B cell receptor for antigen but the precise mechanisms and decision points remain unclear.

Successful vaccination outcomes against antigenically variable pathogens rely on both high levels of affinity maturation and appropriate anatomical locations of B cells and antibodies. Thus, it is crucial to investigate the control mechanisms of the vaccination responses which determine how B cell fate and homing link to the quality of the antibodies produced.

This project will address this challenge specifically by addressing the three questions above to test the following Hypothesis: The phenotype of antigen-specific B cells is distinct at a transcriptomic level and varies with the degree of affinity maturation.

This project will address this hypothesis using well-established wet lab techniques but require the development of bespoke scripts and computational analysis pipelines and would suit a student with prior experience or a clear aptitude for bioinformatics. Next generation sequencing technologies, particularly the 10X system enable high throughput analysis of both antibody sequence and B cell phenotype.

Specifically, this project will leverage these techniques to address the following questions using a transgenic mouse model: