Lymphatic endothelial cells as regulators of adaptive immunity and new targets for immunotherapy

• Applicant: Lothar Dieterich, Ph.D.
• Subject Area: Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 543385151

Lymphatic endothelial cells (LECs) exert multiple functions in immunity, ranging from transport of antigen and leukocytes to direct interaction and regulation of various immune cell types in the lymph node microenvironment. Of note, lymph node LECs have been suggested to inhibit autoreactive T cells, but the underlying molecular mechanisms are not clear. Furthermore, single-cell RNA sequencing has revealed molecular heterogeneity of lymph node LECs and identified several subsets that populate different lymph node sinuses. These LEC subsets also express distinct patterns of potentially immune-regulatory molecules, suggesting that they might affect different immunological processes in the lymph node. For example, we previously found that PD-L1, which is constitutively expressed by LECs in lymph node medullary sinuses and the floor of the subcapsular sinus, can inhibit tumor immunity by inducing apoptosis of tumor antigen-specific CD8+ memory T cells. Importantly, a deeper understanding of LEC – immune cell interactions and their alterations in pathological contexts will not only broaden our general understanding of endogenous immune-regulatory mechanisms but may also lead to the discovery of new biomarkers and immunotherapeutic targets for the treatment of a wide range of diseases. We aim to investigate the immunological functions of several candidate molecules expressed by lymph node LECs that we identified in recent RNA-sequencing screens, namely PD-L1, Vista, CD200 and Bst2, in multiple disease models, including autoimmune and chronic inflammatory diseases. Interestingly, our preliminary data suggest that deletion of lymphatic PD-L1 ameliorates experimental autoimmune encephalitis (EAE), a mouse model of multiple sclerosis, potentially due to its inhibitory effect on regulatory T cells in brain-draining, cervical LNs. In parallel, we propose to generate a comprehensive “atlas” of lymph node LECs at the single cell level, integrating previously published and newly generated datasets representing lymph node LECs in various pathological contexts that are characterized by either a repressed or exhausted immune response (e.g. tumor-draining lymph node LECs, chronic virus infection-associated lymph node LECs) or an overshooting or misguided immune response (e.g. brain-draining lymph node LECs in multiple sclerosis, pancreatic lymph node LECs in type-1 diabetes, skin-draining lymph node LECs in chronic dermatitis). Using bioinformatic approaches, we will predict interactions between LECs and immune cells in the lymph node microenvironment based on these datasets and will select and evaluate further potential targets for tomorrow’s immunotherapy.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Cooperation Partners: Dr. Sarah Mundt; Professorin Dr. Annette Oxenius