Fig. 1: Immunomodulation by ECs in lymph nodes and liver.

Known and putative insights into immunomodulation by endothelial cells (ECs) in lymph nodes and the liver. a | Lymph nodes contain high endothelial venules (HEVs), which express chemokines, adhesion molecules and other surface molecules (addressins) that facilitate the adhesion or recruitment of lymphocytes such as naive T cells (Tn cells). b | During inflammation (indicated by the red background), HEVs (upper panel) and venous ECs (bottom panel) in lymph nodes can recruit various immune cells, such as neutrophils, monocytes and effector T cells, in a selectin-dependent manner. c | In preclinical models of cancer, including breast cancer, melanoma that has metastasized to the lung and pancreatic cancer, anti-angiogenic therapy (AAT) or delivery of LIGHT protein, combined with immune checkpoint blockade (ICB), was found to increase HEV biogenesis, thereby promoting tumour immunity and immunotherapy^78,79,80. d | Interestingly, activated HEVs express additional immunomodulatory genes, which may impair dendritic cell (DC) activation (via reverse CD137–CD137L signalling)⁶⁹, alter macrophage differentiation (via macrophage migration inhibitory factor (MIF)^70,71) or inhibit T cell activation (via thrombospondin 1 (TSP1)⁷²). e | Liver ECs with immunomodulatory properties (these are mostly liver sinusoidal ECs (LSECs)) facilitate tolerance to harmless gut flora-derived antigens through co-inhibition of CD8⁺ T cells via the checkpoint ligand programmed death ligand 1 (PDL1) upon cross-presentation of gut flora-derived antigens via major histocompatibility complex (MHC) class I or through the induction of regulatory T cells (T_reg cells) (upon presentation of gut flora-derived antigens to CD4⁺ T cells by MHC class II). f | LSECs clear immune complexes from the circulation via uptake and degradation. g | Periportal LSECs sense gut bacteria and recruit resident macrophages and lymphocytes through chemokine gradients. Besides zone-specific immunomodulation, LSECs might form a hub for communication with resident macrophages through cytokine signalling, thereby altering macrophage phenotypes in a context-dependent manner. h | In hepatocellular carcinoma, malignant hepatocyte-derived vascular endothelial growth factor (VEGF) induces plasmalemma vesicle-associated protein-positive (PLVAP⁺) tumour ECs (TECs) to form an immunosuppressive niche of folate receptor-β-positive (FOLR2⁺) macrophages and T_reg cells. Therapeutic approaches that break LSEC-mediated immune tolerance can impair liver metastasis in preclinical models of metastatic melanoma, breast carcinoma and colon carcinoma⁹⁷. i | In regions of liver fibrosis, atypical chemokine receptor 1-positive (ACKR1⁺) ECs might recruit and modulate/polarize macrophages through the secretion of differentiation factors such as the protein GAS6, growth arrest-specific protein 6 (GAS6) in a contextual manner. Asterisks indicate recent insights which we considered novel for immunomodulatory EC biology. TCR, T cell receptor.