Antibody-Mediated Immunity: Balancing Durable Protection and Pathogenic Antibody Responses

PROJECT OVERVIEW

Antibodies are secreted by plasma cells (PC) that differentiate from activated B cells. Most PCs are short live; they will die soon after the vaccine or infection are cleared. However, a subset of these cells becomes long-lived and persist for months and even years. These cells provide critical immunity from infections by continuously secreting antibodies at very high rates, up to thousands of antibodies per second per cell. However, when mis-regulated, prolonged survival of PCs can contribute to chronic diseases and autoinflammatory states.

In this project we will focus on understanding where and how long-lived PCs are regulated in vivo.

An intriguing observation has been that while long- and short-lived PCs differ in their lifespan, their phenotype are similar. Why, then, does one subset persist while the other does not? The current dogma posits that PC fate is primarily determined by extrinsic factors: if a PC reaches a niche that supports its survival, it will persist; if not, it will quickly die. A key question remains: what defines the long-lived PC niche, and what types of cells and molecular mechanisms characterize these sites?

To answer these questions, we need robust methods to visualize and interrogate long-lived PC niches in situ. We recently utilized new mouse models and imaging-based approaches that allow us to comprehensively explore this question across organs. With these models we can identify specialized niches that selectively support long-lived PC survival, and we can interrogate their unique cellular and molecular composition. Ultimately, the goal of this project will be to uncover mechanisms that control PC longevity in vivo and to identify settings that tip the balance from protective to potentially harmful responses.

KEYWORDS

Long-lived plasma cells, memory B cells, infection, vaccine, autoimmunity.

TRAINING OPPORTUNITIES

In this project we focus on environmental factors that promote long-lasting antibody responses. This work has broad implications on human health: antibodies are key to protection from re-occurrent infections, but also major drivers of clinically important diseases including autoimmunity and cancer.

The project will include high level training in cutting-edge imaging approaches, including whole organ visualization and quantitative, high-resolution confocal microscopy and quantitative analysis of cell distribution within tissues.

An important strength of the study is that it involves the use of novel mouse models infected with human relevant pathogens or immunized with vaccines. This approach provides the opportunity of directly exploring mechanistic and functional questions, whilst maintaining the physiological relevance to the human disease.

Pending on results, functional advanced genomic approaches (e.g., single cell RNA-seq, spatial transcriptomic and similar techniques) may also be employed.

This is a highly creative and innovative project, which will involve a long learning curve. As such, it is suitable to a student that is motivated by challenges and cutting-edge science, and who is attracted to studies that involve long, complex experiments. The experimental, nature of the work means that it is not suitable for individuals who prefer to have the opportunity to work from home.
Interested candidates are strongly encouraged to contact Prof. Tal Arnon by email directly.

KEY PUBLICATIONS

1. MacLean AJ, Bonifacio Lopes JPP, Oram SL, Mohsen MO, Bachmann MF And Arnon TI. Regulation of pulmonary plasma cell responses during secondary infection with influenza. (2023) Journal of Experimental Medicine Jul 1;221(7):e20232014. PMID: 38661717

2. MacLean AJ, Richmond N, Koneva L, Attar M, Medina CAP, Thornton E, Cruz-Gomes A, El-Turabi A, Bachmann MF, Rijal P, Tan TK, Townsend A, Sansom SN, Bannard O, and Arnon TI. Secondary influenza challenge triggers resident memory B cell migration and rapid relocation to boost antibody secretion at infected sites (2022) Immunity Apr 12;55(4):718-733.e8. doi: 10.1016/j.immuni.2022.03.003.

3. Chauveau A, Pirgova G, Cheng HW, De Martin A, Zhou FY, Wideman S, Rittscher J, Ludewig B, and Arnon TI. 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. PMCID: 32298648

4. Pirgova G, Chauveau A, MacLean AJ, Cyster JG and Arnon TI. Marginal zone SIGN-R1+ macrophages are essential for the maturation of germinal centre B cells in the spleen. (2020) PNAS 18:201921673. PMCID: 32424104

THEMES

Antibody-mediated immunity, infections, autoimmunity

CONTACT INFORMATION OF ALL SUPERVISORS

Tal Arnon

Michael Dustin

Sophia Oram