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

 

Adaptive immune responses are essential for the control of acute infections and for the immunity achieved following prior exposure or vaccination. This process requires that extremely rare antigen-specific B and T cells encounter their cognate antigen, receive context-specific instructive signals from innate cells, establish cognate interactions with each other, and ultimately differentiate in a controlled manner before migrating onwards to their effector sites. While seemingly unlikely, this all occurs with remarkable efficiency largely thanks to a highly evolved guidance system which directs movement of cells in particular differentiation states to specialized niches. Defining the microanatomical structures and mechanisms that instruct cell transition between functional niches, and identifying the signals delivered within these sites, is therefore key to our understanding of adaptive immunity.

Current projects

1. The biology and function of memory B cells in the lung; development, survival and function of resident memory B cells in peripheral tissues: Immunological memory of antibody responses is the basis for most current vaccines. Memory B cells that recirculate and scan the body by migrating between secondary lymphoid organs play key roles in this process. When activated, these cells provide a major source of antibodies which are secreted to the serum, disseminate throughout the body and eventually transude into infected tissues, where they limit disease spreading. However, while this mechanism provides an important protection, it may take time before the levels of antibodies reach the concentration needed to saturate sites of pathogen replication. Considering the fast life cycle of most microbes, this delay remains a major limiting factor in the success of many vaccines. Identifying mechanisms that allow rapid and localized antibody production directly within infected regions may help to overcome this challenge.

In recent years, a new population of non-recirculating resident memory B (BRM) cell subset has been identified in lungs of influenza infected hosts. These cells are located directly near portals of pathogen entry and may therefore represent an important and previously unexplored source of local antibodies. To study these cells, our lab has developed a novel mouse model and advanced imaging procedures allowing us to directly visualize BRM cells in situ, in live lungs of influenza infected mice. We uncovered a new network of innate-adaptive cell interactions that coordinates localised humoral responses, culminating in the recruitment of BRM cells to infected sites and in the accumulation of plasma cells (PCs) within these regions (MacLean A et al. Immunity 2022) (Figure 1). Given that a single PC can produce up to ~1000 antibodies per second, this process may represent a powerful mechanism to dramatically increase local antibody concentrations where they are needed most; at sites that experience the highest viral titers.

Building on our existing mouse models, imaging procedures and ongoing studies, we aim to:

  • Define the cellular and molecular mechanisms that promote differentiation of PCs within infected lungs
  • Test the functional contribution of BRM cells to protective immunity in the lung
  • Explore the roles of resident memory B cells in chronic inflammation in the lung (e.g., asthma)

(Figure 1) 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).

2. The spatiotemporal regulation of adaptive immune cells in the spleen; host response to systemic infections and blood pathogens: The spleen is a major lymphoid organ and the only one to filter the blood. Dysfunctional spleen is associated with increased incidents of sepsis, impaired peripheral-tolerance, and expansion of pathogenic cells. Yet, despite its importance, we know relatively little about the microanatomy of the spleen and how cells move and interact within it. A major challenge to addressing these questions 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 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), thus critically regulating the ability of the host to generate high affinity antibodies and durable memory B cell responses. In our future work, we will continue to explore where and how adaptive immune cells become activated in the spleen and to determine the roles of the 'entry checkpoint' in regulating activation and differentiation of cells.

3. Mechanisms that regulate adaptive immune cell recirculation during homeostasis and inflammation; lymphocytes recirculation in the spleen: An effective adaptive immune system requires that lymphocytes continuously re-circulate between the different secondary lymphoid tissues of the body where they can "search" for cognate antigens, and potentially initiate immune responses. During times of homeostasis, access to secondary lymphoid tissues is also essential for allowing B and T cells to be "educated" by other specialized immune cells, which involves the receiving of pro-survival and tolerance-inducing signals. Over the past decades, the mechanisms of immune cell trafficking toward and through lymph nodes (LNs) have been intensely studied, establishing a well-defined multi-step model of entry and egress. These studies enhanced our understanding of immunology and led to development of therapeutic agents to treat autoimmune diseases. Despite these important advances, our current knowledge of even the basic anatomical structures that support recirculation of lymphocytes in the largest secondary lymphoid organ in our body, the spleen, is very limited. As such, we may potentially be missing important opportunities to develop new therapeutic interventions that aim to block this process.

Using our intravital imaging procedure, we showed that the path into splenic white pulps is mediated via well-defined structures, composed of stroma-coated blood vessels that guide a highly regulated cell movement. These studies also disproved the prevailing hypothesis that entry and egress to the spleen are mediated via the same site, thus establishing that an additional egress specific structure must exist in this organ (Chauveau A. et al., Immunity 2020) (Figure 2).

We aim to:

  • Delineate the molecular basis of entry by identifying signals that attract lymphocytes to the entry paths during steady state and inflammation
  • Identify the elusive egress structures and explore their cellular and molecular composition

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).

PRINCIPAL INVESTIGATOR