Defining follicular dendritic cell provided niche factors important for optimal germinal center reactions

• Applicant: Dr. Konrad Knoepper
• Subject Area: Immunology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521530416

The generation of high-affinity antibody producing cells is an essential part of the adaptive immune response. The formation and maturation of memory B cells and long-lived plasma cells is performed in the germinal center (GC). Dysregulation of GCs can lead to misguided antibody maturation and production, causing autoimmunity or lymphomagenesis. GCs form inside follicles within lymphoid tissues. An integral part of the GC reaction are follicular dendritic cells (FDCs). These mesenchymal cells interact with B cells by presenting antigen complexes and providing chemokine gradients as guiding cues for positioning of B cells during the GC reaction. Although some aspects of FDC contribution to a successful GC reaction are known, many open questions remain. The antigen presenting properties of FDCs differ from other conventional antigen presenting cells (APCs) like dendritic cells or macrophages in several aspects. FDCs present intact antigen complexes stably for weeks or months. How the integrity of antigen complexes is maintained in lymphoid follicles is currently unknown. Furthermore, it is not uncommon for one infection to be followed by another. The dynamics of consecutive antigen capture and presentation by FDCs remains an open question. Is prolonged presentation of one antigen impacted by the introduction of a second antigen to the system? In this proposal we aim to address these fundamental questions. In Aim 1 we will develop a CRISPR-based approach to screen FDCs for genes that influence these processes. In particular, we will define how FDCs establish their dendritic morphology that ensures a large surface area for antigen display and B cell encounter. As a second Aim we will explore the hypothesis that FDCs produce protease inhibitors that help make the follicle an antigen sanctuary. Specifically, we will investigate the contribution of Serpina1 family genes in protecting FDC bound antigens from proteolysis. Finally, in Aim 3 we will decipher antigen presentation dynamics of FDCs for competing antigens. We will ask how the presence of a primary antigen influences FDC capture and presentation of a secondary antigen. Understanding these fundamental aspects of FDC and GC biology can guide further research into more efficient vaccination methods and treatment options for patients.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Jason Cyster