Abstract
Peripheral node addressin (PNAd) marks high endothelial venules (HEV), which are crucial for the recruitment of lymphocytes into lymphoid organs in non-mucosal tissue sites. PNAd is a sulfated and fucosylated glycoprotein recognized by the prototypic monoclonal antibody, MECA-79. PNAd is the ligand for L-selectin, which is expressed on the surface of naive and central memory T cells, where it mediates leukocyte rolling on vascular endothelial surfaces. Although PNAd was first identified in the HEV of peripheral lymph nodes, recent work suggests a critical role for PNAd in the context of chronic inflammatory diseases, where it can be used as a marker for the formation of tertiary lymphoid organs (TLOs). TLO form in tissues impacted by sustained inflammation, such as the tumor microenvironment where they function as local sites of adaptive immune cell priming. This allows for specific B- and T-cell responses to be initiated or reactivated in inflamed tissues without dependency on secondary lymphoid organs. Recent studies of cancer in mice and humans have identified PNAd as a biomarker of improved disease prognosis. Blockade of PNAd or its ligand, L-selectin, can abrogate protective antitumor immunity in murine models. This review examines pathways regulating PNAd biosynthesis by the endothelial cells integral to HEV and the formation and maintenance of lymphoid structures throughout the body, particularly in the setting of cancer.
Highlights
Peripheral node addressin (PNAd) marks high endothelial venules (HEV), which are crucial for the recruitment of lymphocytes into lymphoid organs in non-mucosal tissue sites
PNAd is the ligand for L-selectin, which is expressed on the surface of naive and central memory T cells, where it mediates leukocyte rolling on vascular endothelial surfaces
PNAd was first identified in the HEV of peripheral lymph nodes, recent work suggests a critical role for PNAd in the context of chronic inflammatory diseases, where it can be used as a marker for the formation of tertiary lymphoid organs (TLOs)
Summary
Lymphotoxin beta receptor (LTβR) signaling drives expression of adhesion molecules and chemokines involved in the recruitment of circulating lymphocytes into lymphoid organs, including CCL21, CXCL13, MAdCAM-1, and peripheral node addressin (PNAd) [1]. Expression of LTβR on endothelial cells in peripheral lymph nodes is required for their development into high. LTα1β2 controls luminal PNAd expression, while LTα3 controls abluminal PNAd expression [1] These differences in ligand function appear to relate to their impact on the level of GlcNAc6ST expression by endothelial cells. Reports suggest that neither cell type is required for HEV differentiation [4], it has been observed that Rag−/− mice exhibit decreased expression of GlcNAc6ST-2 compared to WT mice [6]
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