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 (BRMs) 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 is not unclear.
Preliminary data:
We have recently developed a novel mouse model, fluorescent probes and advanced 2-photon imaging procedures to directly trace BRM 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 BRM cells are evenly distributed throughout the lung parenchyma, where they display modest migratory capacity and a localized probing behaviour. However, following rechallenge, BRM 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 leading to induction of chemotactic factors that promoted BRM cell localization within sites of infection.
Hypothesis:
We propose that BRM 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.
Importance:
BRM cells have only recently been discovered. It is likely that the identification of these cells lagged because of the prevailing hypothesis that B cells do not need to travel to sites of infection to exsert their function; they can instead secret antibodies and rely on the blood to carry them to infected sites. However, while this powerful process has been successfully exploited for the development of many vaccines, some pathogens remain challenging. As such, the discovery that BRM cells exist and that they can differentiate into antibody producing PCs locally within infected sites, is an important advance that may be key for developing novel vaccine strategies. Moreover, while BRM cells may be beneficial for protection from pathogens, their dysregulated development or activation may contribute to antibody-mediated diseases, including autoimmunity, allergy and tumours. Defining factors that promote PC differentiation in peripheral sites may therefore help to negate their development in the context of pathological conditions.
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, such as live imaging using 2-photon microscopy, whole organ visualization using light sheet microscopy 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) BRM 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) will 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.
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