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The main focus of the lab is to understand how humoral immune responses are regulated within the spleen.

Current projects

1.  How do resident memory B cells and plasma cells regulate immunity in the lung? Infection with influenza virus leads to development of resident memory B (BRM) cells and plasma cells that persist in the lung tissue for many months. The strategic positioning of these cells near portals of viral entry suggests a superior capacity to promote rapid increase in local antibody concentrations. We recently developed a novel mouse model, fluorescent probes and advanced imaging procedures to directly visualize and study BRM cells and plasma cells in situ, in live lungs of influenza infected mice (Maclean AM et al. Immunity 2022). Our study reveals that upon re-challenge, an alveolar macrophage orchestrated cascade of events leads to the recruitment of BRM cells to sites of infection, a process which culminates in the differentiation of antibody producing plasma cells at these regions. We propose that promoting local differentiation of plasma cells directly where viral replication occurs represents a powerful mechanism to efficiently block viral spreading. In future work we aim to test this hypothesis and to identify specific molecular and cellular mechanisms that regulate this process. In addition, we will ask how the development of BRM cells in the lung and potentially other sites may promote chronic diseases, where antibody production is harmful.

This movie illustrates low motility of alveolar resident memory B cells prior to rechallenges. A resident memory B cells performing a surveillance behaviour near an alveoli.

Confocal microscopy of a lung section, 4 days after being rechallenged with an influenza virus. Resident memory B cells (red) and newly generated plasma cells (yellow) can be seen in very close proximity to infected cells (light blue)

Confocal microscopy of a lung section, 4 days after being rechallenged with an influenza virus. Resident memory B cells (red) and newly generated plasma cells (yellow) can be seen in very close proximity to infected cells (light blue).

2.  Where/how initial T cell activation occurs in the spleen? The microanatomical organization of secondary lymphoid organs evolved to ensure that rare antigen-specific T and B cells receive activation signals in a timely and context-dependent manner. However, the current lack of understanding of how cells enter the splenic tissue limits our ability to accurately explore where/how immune responses are initiated within this organ. We recently demonstrated that an ‘entry-checkpoint’ located at the gateway into splenic white-pulps exists (Chauveau A. et al., Immunity 2020). We further showed that a selected subset of tissue resident macrophages that occupies nearby niches plays a critical role in promoting gremial centre B cell responses (Pirgova G. et al., PNAS 2020). Our future work will aim to test the hypothesis that this ‘entry checkpoint’ regulates the first step of lymphocyte activation and to define how instructive signals that are delivered in these sites shape systemic adaptive immune responses.

 

3.  How do lymphocytes egress splenic white-pulps? The largest reservoir of native T and B cells in our body is located inside the splenic white-pulp. Yet, little is known about how lymphocytes egress this niche. A major challenge to addressing this question has been the lack of appropriate technology for examining cell movement inside this large organ. Our group pioneered cutting-edge imaging approaches that give us a unique view of immune cell behaviour within intact spleens of living mice (Arnon TI et al. Nature 2013). Utilizing this approach, we recently visualized lymphocyte entry into the spleen and demonstrated that in contrast to previous models, the entry structures that promote migration into white pulps, do not support egress (Chauveau A. et all., Immunity 2020). We predict that an unidentified egress site of naïve T cells must exist in the spleen, and we aim to identify the location, cellular composition and molecular mechanisms that underline these routes. 

This movie illustrates the architecture of the entry paths into T zones. 2-photon intravital imaging of newly transferred T cells (in green) migrating into the splenic white pulp. Endogenous T cells are shown in red. Movies were imaged 24h post transfer.

This movie illustrates the perivascular nature of the entry paths. 2-photn intravital imaging of spleens showing red blood cells (in green) passing at very high speeds inside tracks of T cells (in red). 

 

4.  Can we improve CAR-T cell-based therapy by manipulating the migratory potential of T cells? In cell therapy, limited trafficking of engineered T cells to tumors represents a major roadblock for solid tumor treatment. Previous studies partially overcame this hurdle by intratumoral injection of cells or overexpression of a specific migration-promoting receptors. However, these approaches are limited to tumors in accessible locations and which express specific chemoattractant. We seek to test whether modifications that alter the overall responsiveness of T cells to migratory signals can enhance their infiltration to solid tumors.

PRINCIPAL INVESTIGATOR

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