Investigating how RNA helicase activity modulates antibody immunity

(Please contact the Group Leader proposing this project directly BEFORE submitting your application to the University of Cambridge Graduate Portal to discuss possible funding options)

Adaptive immunity is characterized by gradual, though highly specific and effective immune responses against pathogens. B-cells are responsible for the production of a diverse repertoire of antibodies, through class switch recombination (CSR) and somatic hypermutation (SHM). These processes rely on precise regulation of gene expression and it has become increasingly appreciated that they are also strongly dependant on regulation at the RNA level. RNA helicases are a class of ubiquitous RNA-binding proteins (RBPs) that hold great promise as therapeutic targets. They are mostly known for their roles in viral infection and cancer development, but recent findings indicate that RNA helicases are also important regulators of immunity. Our previous work has shown that the RNA helicase DDX1 is required to initiate CSR, the process by which B-cells produce antibodies of different effector functions (Ribeiro de Almeida et al, 2018). At the cellular level, CSR is part of a developmental program that promotes the differentiation of activated B-cells into antibody-producing plasma cells. This program is regulated in time and space, comprising of an early response that confers some level of antibody protection, and subsequent formation of highly specialized microanatomical structures called germinal centers (GC) where SHM occurs, to enhance antibody affinity and provide long-lasting immunity.

Antibody mediated immunity is central to health and disease, and the emergence of pathogenic B-cell clones associated with defective GC reactions can lead to autoimmunity or B-cell lymphoma. The aim of this PhD project is to establish a novel molecular tool that allows control over RNA helicase expression at the protein level, in the B-cell lineage. This will allow dynamic modulation of RNA helicase activity by fine-tuning protein abundance in a time-resolved manner, i.e. during early stages of B-cell activation, GC formation and maintenance. The successful PhD candidate will be trained in molecular and cellular biology techniques, including in vivo analysis of the immune system using mouse models, flow cytometry and imaging. These studies will uncover new roles for RNA helicase activity during B-cell immune responses, with the potential to inform new therapeutic strategies for immune disease.