Kennedy Trust Prize Studentships
Spatiotemporal regulation of adaptive immune responses; defining the molecular and cellular basis for immunity against infectious diseases
- Project No: NCKIR8
- Intake: 2022 KIR Non Clinical
Supervisor: Professor Tal I Arnon
Co-Supervisor: Professor Marco Fritsche
The adaptive immune system provides protection against a wide range of pathogenic microbes. In its most basic level, this system is effective because it developed the capacity to evolve through spontaneous gene mutations, leading to the generation of an enormous repertoire of B and T cells. On a population level, this means that the adaptive immune system covers in principle every antigen that could possibly evolve. However, to utilize this system successfully in a physiological setting, additional mechanisms have evolved. While in previous decades scientists mostly concentrated on exploring the molecular mechanisms underpinning B and T cell activation in vitro, recent research over the past 20 years has largely shifted to the understanding of adaptive immune responses within living organisms. These efforts revealed that expressing the right B or T cell receptor is not enough and that to mount an effective immune response, extremely rare antigen specific B and T cells must first find their cognate antigen and then engage in a series of interactions with multiple cell types in a coordinated manner. These dynamic events occur with remarkable accuracy and efficiency, largely thanks to a highly evolved guidance system that allows cells to navigate between microanatomical niches, where specialised cells provide T and B cells with survival, activation, and differentiation cues.
Our lab aims to understand how adaptive immune responses are orchestrated in vivo. We ask how migrating lymphocytes reach functional compartments within secondary lymphoid organs, how they communicate with various immune and non-immune cells within these sites, how they leave the priming niches and localise to peripheral infected tissues, and how all of this culminates in an effective immune response. To explore these questions, we employ a range of quantitative cutting-edge microscopy modalities including 2-photon intravital analysis, multi-parameter super-resolution airyscan confocal microscopy, and light sheet. We will combine these approaches with an array of mouse models, genomic techniques, and functional assays that allow us to directly visualise immune responses in real time within the living organs and to relate dynamic analysis to molecular mechanisms. In this project we will focus on investigating how adaptive immunity against pulmonary infections and vaccination are orchestrated. Ultimately, these studies will lead to improved design of vaccines and to the development of immuno-modulatory therapeutics with greater specificity and efficacy.
Adaptive immunity, pulmonary infection, imaging, vaccine.
In this project, we focus is on mechanisms that regulate the development and function of adaptive immunity in response to pulmonary infection and vaccination. While these studies have important clinical implications, our goal is to delineate basic mechanisms that underpin these processes. It is therefore suitable for a student that has keen interest in basic immunology and is excited about testing conceptual biological questions in vivousing mouse models. The project will involve a variety of methods with a combination of advance imaging techniques, functional and genomic approaches. Whilst the research will be primarily carried out in the main supervisor’s lab, it will greatly benefit from the unique technological advances in Prof Fritzsche’s lab, which is developing ways to analyse cell-cell interactions with unprecedented spatiotemporal sensitivity. This is a highly creative and innovative project. To be successful in these studies will involve learning and perfecting complex expertise, including intravital imaging and other complicated in vivo assays. It is therefore best suited for an intelligent and energetic candidate that is motivated by spending time at the bench developing their skills and solving problems, whilst constantly expanding his/her knowledge in parallel through ongoing scientific discussions, receiving/providing scientific feedback, reading relevant literature, and interacting with the wider scientific community. Interested candidates are strongly encouraged to contact Dr Tal Arnon by email directly.
- 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) PNAS18:201921673.
- 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) Science352(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.
- Li D*, Colin-York H*, Barbieri L*, Javanmardi Y, Guo T, Korobchevskaya K, Moendarbary E, Li D, Fritzsche M, Astigmatic Traction force microscopy (aTFM). (2021) Nature Communications 12;12(1):216853.