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Exploring the molecular basis of adjuvant function and priming of immune responses in the spleen (KTPS-NC-3)


Kennedy Institute of Rheumatology

, Friday, January 08, 2021 Funded PhD Project (Students Worldwide)

About the Project

The adaptive immune system provides critical protection from a diverse range of rapidly evolving microbes. A key step in initiating adaptive immunity involves the delivery of antigens into secondary lymphoid organs, including the lymph nodes and the spleen. This process ensures that rare antigen specific T and B cells that scan these organs are able to locate even low levels of their cognate antigen and to become activated before the invading pathogen established lethal infection. Effective delivery of antigens to secondary lymphoid organs greatly depends on the mobilization of migratory antigen presenting cells (APCs) from the site of immunization/infection into the lymphoid tissue. In the case of lymph nodes, this process is primarily mediated via recruitment of dendritic cells and other myeloid subsets that travel via the lymph and enter lymph nodes. However, how these events are regulated in the spleen remains poorly understood. Unlike lymph nodes, the spleen does not drain the lymph, it filters the blood and it therefore does not recruit lymph-borne APCs. Furthermore, the structures that support entry into the splenic lymphoid tissue is fundamentally different than those that mediate entry into lymph nodes, further suggesting specific mechanisms must have evolved. Because the spleen is the largest lymphoid organ in our body, the overall contribution of this organ to immune responses is significant. Thus, defining mechanisms that promote splenic immunity may help to utilize the the enormous potential of this organ when vaccinating against certain challenging pathogens.

In this project, we aim to explore mechanisms of transport of particulate antigens from immunologically challenged mucosal sites to the spleen. Our goal is to define APC subsets that are able to reach the spleen from infected sites and to identify the mechanisms they use to enter and prime immune responses in the spleen. We will examine how certain types of stimuli that are often used in vaccine adjuvants may enhance or inhibit these events and we will determine the relevance of specific pathways to induction of protective immunity against influenza virus. The overall goal of the project is to understand the molecular basis of APC migration from the lung to the spleen and to explore the functional significance of these pathways during immunization.

Vaccine, spleen, adjuvant, influenza infection

TRAINING OPPORTUNITIES:
In this project you will learn to combine advanced imaging techniques with a variety of immunological assays to interrogate the relationship between immune cell migration and function. The project is suitable for a student that is motivated by basic science and is excited about dissecting molecular mechanisms that regulate cell trafficking in vivo, using transgenic mouse models. Interested candidates are encouraged to contact Dr. Tal Arnon by email directly.


References

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.
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.
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.
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.
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.

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