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Kennedy Trust Prize Studentships

  • Project No: KTPS-NC-2
  • Intake: 2021 KTPS-NC

PROJECT OUTLINE

Influenza virus is a common airborne pathogen that continues to present a significant medical challenge causing over 3 million cases of critical illness and up to 500,000 deaths per annum. Efforts to develop vaccines against influenza have been hampered by the rapid generation of new escape variants each year. This is largely due to the fact that antibody responses against influenza, as well as those induced by vaccination, often exert selective pressure on the virus giving rise to escape variants. Importantly, accessibility of antibodies to the infected mucosal site also plays a central role in protection. As such, inducing cross-reactive antibody responses at the site of infection could help prevent the emergence and dissemination of novel influenza variants.

Following primary infection or vaccination, high affinity antibodies are generated in the germinal centre (GC) reaction, a process that involves multiple rounds of selection driven by AID-dependent class switching and somatic hypermutation. Memory B cells that emerge through this pathway recirculate between secondary lymphoid organs, continuously scanning the body for secondary infection. However, during certain pulmonary viral diseases, a large number of memory B cells can also be found in peripheral sites within the infected tissue. These resident memory B cells (Brm) do not appear to circulate but instead they persist in the tissue for prolonged periods of time after pathogen clearance. Recent studies suggest that in the context of influenza infection, these cells may have a superior capacity to generate cross-reactive antibodies to various influenza strains. Due to its location and broad specificity, manipulation of tissue-resident B cells may be ideally suited for the induction of localised, cross-reactive antibody responses. However, despite recent advances the relative contribution of Brm cells to protection from re-challenge by influenza strains and the mechanisms regulating their development and function remain unknown.

In this project we will aim to address these questions by using new mouse models in which fluorescent labelling of memory B cells allows their visualization in live sections of infected lungs. These imaging efforts will be combined with hemagglutinin probes we have developed to selectively identify and cell sort influenza-specific B cell subsets allowing analysis of their unique expression profiles. We hope that findings from these studies will not only help to improve our basic understanding of B cell biology but may also help in the development of novel vaccines and treatments to chronic diseases that are mediated by locally produced pathogenic antibodies.

KEYWORDS

Memory B cells, influenza, imaging, vaccine.

TRAINING OPPORTUNITIES

In this project we focus is on mechanisms that regulate the development and function of local memory humoral responses in the lung of influenza-infected mice. However, the broader implications of this work go beyond the specific response to influenza; it aims to understand the unique and understudied biology of resident memory B cells in peripheral sites. It is therefore suitable for a student that has keen interest in basic immunology and is excited about testing conceptual biological questions in vivo using mouse models. The project will involve a variety of methods with a combination of advance imaging techniques and functional genomic approaches. This is a highly creative and innovative project, so a suitable student must be the kind that is motivated by challenges and cutting-edge science. Interested candidates are encouraged to contact Dr. Tal Arnon by email directly.

KEY PUBLICATIONS

  1. Anne Chauveau, Gabriela Pirgova, Cheng HW, Angelina De Martin, Zhou FY, Sarah Wideman, Jens Rittscher, Burkhard Ludewig, and Tal I Arnon. Visualisation of T cell migration in the spleen reveals a network of perivascular pathways that guide entry into T zones. (2020) Immunity 19;52(5):794-807.
  2. Gabriela Pirgova, Anne Chauveau, Andrew J MacLean, Jason G Cyster and Tal I Arnon. Marginal zone SIGN-R1+ macrophages are essential for the maturation of germinal centre B cells in the spleen. (2020) PNAS 18:201921673.
  3. Andrea Reboldi, Tal I Arnon, Laura B Rodda, Atakilit A, Dean Sheppard and Jaons G Cyster. B cell interaction with subepithelial dendritic cells in Peyer's patches is critical for IgA production. (2016) Science 352(6287):aaf4822. 
  4. Tal I Arnon, Bob M Horton, Irina L Grigorova and Jason G Cyster. Visualization of splenic marginal zone B cell shuttling and follicular B cell egress. (2013) Nature 493(7434):684-8. 
  5. Emily E. Thornton,  Mark R. Looney,  Oishee Bose,  Debasish Sen,  Dean Sheppard,  Richard Locksley, Xiaozhu Huang,  Matthew F. Krummel. Spatiotemporally separated antigen uptake by alveolar dendritic cells and airway presentation to T cells in the lung. (2012) JEM 209 (6): 1183–1199.

CONTACT INFORMATION OF ALL SUPERVISORS

tal.arnon@kennedy.ox.ac.uk

emily.thornton@ndm.ox.ac.uk

 

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