We are interested in the mechanisms governing immune cell interaction, which are crucial for mounting effective immune responses. The research brings together immunology, cell biology and genetics to understand immune synapse formation, endocytosis and antigen presentation in B cells and dendritic cells. Understanding these fundamental processes in immune cell biology is critical for therapeutic discoveries and improvements in vaccine design, malignancy and autoimmunity.
What regulates antigen-BCR trafficking following antigen endocytosis?
Through large-scale genomic and proteomic studies, we have identified and validated over 70 positive and negative regulators of B cell antigen endocytosis and are currently investigating the molecular mechanisms of different groups of these including cytoskeletal proteins, signalling cascades and intracellular trafficking regulators.
How do antigen uptake, trafficking and presentation compare between B cells and other antigen presenting cells?
We aim to characterise differences in regulation of antigen trafficking between B cells, where antigen endocytosis is receptor-mediated, and other professional antigen presenting cells including macrophages and dendritic cells, where antigen is acquired through a broader range of endocytic pathways.
How do trafficking regulators affect B cell development?
We have established a fast and efficient CRISPR/Cas9 bone marrow chimera model, in which we can interrogate how deleting a gene of interest affects the development of different immune cell populations. For example, we could show that Endophilin A2-mediated trafficking is essential for the development of marginal zone B cells, while autophagy regulators are required across the immune system.
How are signalling and antigen uptake coordinated?
Upon antigen binding, BCRs initiate downstream signalling as well as endocytosis; these processes must be coordinated in space and time, which likely involves numerous signalling, scaffolding and cytoskeletal proteins. We are interested in the role post-translational modifications, specifically ubiquitination, play in regulating this process.
How are these mechanisms altered in autoimmunity and malignancy? What role does trafficking dysregulation play in malignancy?
Using whole-genome CRISPR/Cas9 screening data, we have identified distinct requirements for endocytic and trafficking regulators in different B cell malignancies. We are currently investigating molecular mechanisms driving this essentiality in chronic lymphocytic leukaemia and multiple myeloma. These could provide potential therapeutic targets, particularly important in patients with limited response to current therapies.
What regulates antigen-BCR trafficking following antigen endocytosis?
Through large-scale genomic and proteomic studies, we have identified and validated over 70 positive and negative regulators of B cell antigen endocytosis and are currently investigating the molecular mechanisms of different groups of these including cytoskeletal proteins, signalling cascades and intracellular trafficking regulators.
How do antigen uptake, trafficking and presentation compare between B cells and other antigen presenting cells?
We aim to characterise differences in regulation of antigen trafficking between B cells, where antigen endocytosis is receptor-mediated, and other professional antigen presenting cells including macrophages and dendritic cells, where antigen is acquired through a broader range of endocytic pathways.
How do trafficking regulators affect B cell development?
We have established a fast and efficient CRISPR/Cas9 bone marrow chimera model, in which we can interrogate how deleting a gene of interest affects the development of different immune cell populations. For example, we could show that Endophilin A2-mediated trafficking is essential for the development of marginal zone B cells, while autophagy regulators are required across the immune system.
How are signalling and antigen uptake coordinated?
Upon antigen binding, BCRs initiate downstream signalling as well as endocytosis; these processes must be coordinated in space and time, which likely involves numerous signalling, scaffolding and cytoskeletal proteins. We are interested in the role post-translational modifications, specifically ubiquitination, play in regulating this process.
How are these mechanisms altered in autoimmunity and malignancy? What role does trafficking dysregulation play in malignancy?
Using whole-genome CRISPR/Cas9 screening data, we have identified distinct requirements for endocytic and trafficking regulators in different B cell malignancies. We are currently investigating molecular mechanisms driving this essentiality in chronic lymphocytic leukaemia and multiple myeloma. These could provide potential therapeutic targets, particularly important in patients with limited response to current therapies.
