CRC1366

Lymph nodes (LNs) are primary sites for encounters between antigen present in the lymph, antigen-presenting cells and lymphocytes. Consequently, they are crucial for the initiation and regulation of adaptive immune responses. Lymph flow, immune cell migration and positioning within LNs, as well as antigen-dependent interactions are orchestrated by stromal cells in the LN microenvironment, including lymphatic endothelial cells (LECs). Recent single-cell RNA-sequencing studies have identified subsets of LN LECs which locate to distinct lymphatic sinuses. In particular LECs located in the floor of the subcapsular sinus (fLECs) and in medullary sinuses (mLECs) regulate antigen access to the LN parenchyma as well as entry and exit of immune cells through release of chemotactic cues and expression of adhesion molecules. Additionally, LN LECs directly control lymphocyte activation and survival through antigen presentation and expression of immune checkpoint molecules, such as PD-L1. Consequently, LN LECs have been implicated in the maintenance of peripheral self-tolerance in steady-state. However, the precise role of LEC-expressed PD-L1 and other immune-regulatory molecules expressed by LN LECs in pathological contexts is not known.
In this project, we are dissecting the precise function of lymphatic PD-L1 on T cell responses in the context of tumor growth, chronic inflammatory diseases, and autoimmunity. Furthermore, using single-cell RNA-sequencing in combination with cellular interaction prediction we aim to unravel additional immune-regulatory pathways activated by LN LECs that may serve as future therapeutic targets to either enhance T cell response or to re-establish tolerance and LN homeostasis.