RNA binding proteins regulate immune responses

Theme: Bioscience for Health

The germinal centre (GC) within lymph nodes is a site of intense proliferation by lymphocytes following infection. Upon entry into the GC B lymphocytes acquire an apoptosis sensitive phenotype, undergo immunoglobulin class switching, somatic mutation and selection for high affinity antibody. When B cells exit the GC they may differentiate to become antibody secreting plasma cells or memory B cells, which are typically long-lived cells. At present the molecular mechanisms which regulate this lineage choice are the subject of intensive investigation because of their importance for vaccination and also when these mechanisms are corrupted B cells can undergo transformation to lymphoma and myeloma.

The molecular regulation of proliferation and differentiation requires dynamic coordination of signal transduction pathways with transcriptional and post-transcriptional control of RNA. Our work and that of others shows that this principle underpins the biology of activated B cells in the GC response.

A principal mechanism for regulating RNA abundance and function is through its interaction with specific proteins. The student will test the role of sequence specific RNA binding proteins in B cell activation and the GC response by using a combination of mouse genetics and molecular biology including high throughput sequencing and bioinformatics.

We have evidence that the RNA binding proteins are essential in the GC response. We propose they mediate the rapid removal of mRNA encoding lineage specific transcripts promoting class switch recombination, differentiation into the GC cell and facilitating somatic hyper-mutation. In this study we propose to test the hypothesis that specific RNA binding proteins mediate this function in B cells. We will specifically mutate the genes in B lymphocytes in vivo using a conditional gene targeting approach. The development and function of B cells will then be measured in both naïve and immunized mice. Conditional targeting will be achieved using mb1Cre (B cell specific) and AIDCre (expressed only in activated B cells).

The biology of RNA binding proteins is fast emerging as a major layer of control in all biological processes, but the field lags considerably behind the field of transcription factors. Thus, there is an excellent opportunity for novel discovery relevant to basic bioscience. There is also the potential to discover new processes that contribute to the development of lymphoma and myeloma.

This work will involve training in the use of state of the art conditional gene expression systems in vivo using mouse models; cell biology: molecular biology and bioinformatics.