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Resident memory B cell responses in the lung; immunity against pulmonary pathogens

  • Project No: KIR-AfOx-01
  • Intake: 2025 KIR AfOx

Immunological memory of antibody responses is critical for the ability of the host to cope with secondary infections and is the basis for the development of most current vaccines. Memory B cells can be found in the circulation, where they are thought to migrate between secondary lymphoid organs scanning the body for secondary infection. However, recent studies have shown that during certain pulmonary diseases a large number of resident memory B cells can also be found in peripheral sites within the infected tissue. These cells do not circulate, but instead persist in the lung for prolonged periods of time. The strategic positioning of resident memory B cells near portals of viral entry suggests a superior capacity to promote rapid increase in local antibody concentrations and to confer long-lasting protection from infection. However, the mechanisms that regulate reactivation of these cells have not been elucidated and their functional contribution to antibody responses remains poorly defined.

We have recently developed a novel mouse model, fluorescent probes and advanced 2-photon imaging procedures to directly trace resident memory B cells, plasma cells (PCs) and influenza infected cells in situ, in live lungs of influenza infected mice (MacLean AM et al. Immunity 2022). We showed that prior to rechallenge, many resident memory B cells are evenly distributed throughout the lung parenchyma, where they display modest migratory capacity and a localized probing behaviour. However, following rechallenge, resident memory B cells dramatically increase their motility and quickly accumulate in regions of infection. Four days later, PCs appear to develop within sites of viral infection. This process largely depends on alveolar macrophages, which trigger a cascade of events, including NK cell activation, leading to induction of chemotactic factors that promoted resident memory B cell localization within sites of infection (MacLean AM et al. JEM 2024).

We propose that resident memory B cells differentiate into PCs directly where viral replication occurs, and we suggest that this process rapidly and dramatically increases localized antibody concentrations, potentially blocking the virus before it has a chance to spread. In this project, we will test this hypothesis and explore the type of signals that drive PC differentiation in these unusual sites.

KEYWORDS

Influenza, lung, antibody, resident memory 

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; they aim to understand the unique 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 include high level training in cutting-edge imaging approaches, potentially including live imaging using 2-photon microscopy, whole organ visualization and quantitative, high-resolution confocal microscopy-based analysis.

An important strength of the study is that it involves the usage of novel mouse models infected with mouse-adapted human influenza strains. This approach provides the opportunity of directly exploring mechanistic and functional questions, whilst maintaining the physiological relevance to the human disease. In line with this notion, recent studies have shown that influenza specific (and other viral induced) resident memory B cells are frequently found in human lungs.

Pending on results, functional advanced genomic approaches (e.g., single cell RNA-seq, spatial transcriptomic and similar techniques) may also be employed.

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 strongly encouraged to contact Prof. Tal Arnon by email directly.

KEY PUBLICATIONS

  1. Maclean AJ, Bonifacio Lopes JPP, Oram SL, Mohsen MO, Bachmann MF And Arnon TI. Regulation of pulmonary plasma cell responses during secondary infection with influenza. (2023) Journal of Experimental Medicine Jul 1;221(7):e20232014. PMID: 38661717
  2. MacLean AJ, Richmond N, Koneva L, Attar M, Medina CAP, Thornton E, Cruz-Gomes A, El-Turabi A, Bachmann MF, Rijal P, Tan TK, Townsend A, Sansom SN, Bannard O, and Arnon TI. Secondary influenza challenge triggers resident memory B cell migration and rapid relocation to boost antibody secretion at infected sites (2022) Immunity Apr 12;55(4):718-733.e8.  doi: 10.1016/j.immuni.2022.03.003.
  3. Chauveau A, Pirgova G, Cheng HW, De Martin A, Zhou FY, Wideman S, Rittscher J, Ludewig B, and Arnon TI. 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. PMCID: 32298648 
  4. Pirgova G, Chauveau A, MacLean AJ, Cyster JG and Arnon TI. Marginal zone SIGN-R1+ macrophages are essential for the maturation of germinal centre B cells in the spleen. (2020) PNAS 18:201921673. PMCID: 32424104

THEMES

Influenza virus, pulmonary infections, antibody-mediated immunity, resident memory B cells

CONTACT INFORMATION OF ALL SUPERVISORS

tal.arnon@kennedy.ox.ac.uk

michael.dustin@kennedy.ox.ac.uk

The Kennedy Institute is a proud supporter of the Academic Futures scholarship programme, designed to address under-representation and help improve equality, diversity and inclusion in our graduate student body.  The Kennedy and the wider University rely on bringing the very best minds from across the world together, whatever their race, gender, religion or background to create new ideas, insights and innovations to change the world for the better. Up to 50 full awards are available across the three programme streams, and you can find further information on each stream on their individual tabs (Academic futures | Graduate access | University of Oxford).

How to Apply

Please contact the relevant supervisor(s), to register your interest in the project, and the departmental Education Team (graduate.studies@ndorms.ox.ac.uk), who will be able to advise you of the essential requirements for the programme and provide further information on how to make an official application. 

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online and the DPhil or MSc by research will commence in October 2025.

Applications should be made to the following programme using the specified course code. 

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.

Interviews to be held week commencing 13th January 2025.