Mapping the Toll roads: visualizing the spatial and functional segregation of endosomal Toll-like receptors

• Applicant: Dr. Olivia Majer
• Subject Area: Immunology ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 547934027

The innate immune system uses a limited set of germline-encoded pattern recognition receptors to detect and respond to pathogen-associated features. The subcellular location from where these receptors get activated has a critical impact on their signaling response, making spatial control a fundamental principle of immune regulation. My research integrates the fields of immunology and cell biology to investigate how the spatial organization of nucleic acid-sensing Toll-like receptors (TLRs) dictates their signaling behavior. Sensing of microbial nucleic acids is crucial for effective immunity, but poses the risk of self-recognition and autoimmunity. To successfully discriminate between self and non-self, TLRs limit exposure to host-derived ligands by restricting their localization to intracellular endosomal compartments. Several mechanisms cooperate to establish this compartmentalization, however, how signaling of these potentially self-reactive receptors is integrated into the endomembrane network is still ill defined. Identifying the precise subcellular compartments in which TLRs operate and how the complex endosomal landscape shapes their signaling function is of utmost importance to fully understand how TLRs are regulated to avoid self-recognition, yet provide protection against infection. Here, we aim to investigate these fundamental aspects of TLR biology by leveraging our expertise in state-of-the-art super-resolution microscopy to visualize and track TLRs within human and mouse immune cells, providing unprecedented insights into immune regulation. Our preliminary data indicate distinct subcellular localizations and unique interactions of TLRs with endosomal proteins, suggesting unique functions among TLR members. Expanding on these discoveries, we will comparatively dissect the specific sorting and signaling mechanisms of all nucleic acid-sensing TLRs (3, 7/8, 9, and 13) to discover new principles of how receptor trafficking and endosome perturbations impact immune signaling. This work will provide a groundbreaking conceptual framework for understanding how the subcellular organization of TLRs governs their signaling behavior and self-reactivity, with implications for autoimmune diseases, infection, and inflammation.

• DFG Programme: Research Grants