|, CD62L, LAM1, LECAM1, LEU8, LNHR, LSEL, LYAM1, PLNHR, TQ1, selectin L|
L-selectin, also known as CD62L, is a cell adhesion molecule found on the cell surface of leukocytes and the preimplantation embryo. It belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups containing a Sialyl LewisX (sLeX) determinant. L-selectin plays an important role in both the innate and adaptive immune responses by facilitating leukocyte-endothelial cell adhesion events. These tethering interactions are essential for the trafficking of monocytes and neutrophils into inflamed tissue as well as the homing of lymphocytes to secondary lymphoid organs. L-selectin is also expressed by lymphoid primed hematopoietic stem cells and may participate in the migration of these stem cells to the primary lymphoid organs. In addition to its function in the immune response, L-selectin is expressed on embryonic cells and facilitates the attachment of the blastocyst to the endometrial endothelium during human embryo implantation.
L-selectin is composed of multiple structural regions: an N-terminus C-type lectin domain, an adjacent epidermal growth factor-like domain, two to the consensus repeat units homologous to those found in C3/C4-binding proteins, an extracellular cleavage site, a short transmembrane domain, and a cytoplasmic tail. It is cleaved by ADAM17.
- GlyCAM-1, found in the high endothelial venules of the lymph nodes.
- CD34, found on endothelial cells.
- MadCAM-1, found on endothelial cells of gut-associated lymphoid tissue.
- PSGL-1, binds with low affinity.
L-selectin is expressed constitutively on most circulating leukocytes. Over time, these molecules are released through the process of ectodomain shedding and are replaced by newly synthesized L-selectin proteins. Ectodomain shedding is largely accomplished through cleavage by ADAM17.
L-selectin is expressed on naive T cells and is rapidly shed following T cell priming. L-selectin expression is re-activated in cytotoxic T cells once they exit the lymph node. Mature central memory T cells express L-selectin while effector memory cells do not. L-selectin is also expressed by naive B cells, with the loss of L-selectin distinguishing activated B cells destined to differentiate to antibody-secreting cells
L-selectin is expressed on circulating neutrophils and is shed following neutrophil priming. Expression of L-selectin in neutrophils decreases with neutrophil aging. Classical monocytes express high levels of L-selectin while in circulation. Shedding of L-selectin from monocytes occurs during trans-endothelial migration.
L-selectin expression is also observed on oocytes and early-stage embryos. Blastocysts express L-selectin following, but not prior to emergence from the zona pellucida. An increase in L-selectin expression is observed when both the blastocyst and cytotrophoblast attach to the endometrium. L-selectin expression decreases by the 17th week of pregnancy, and remains low or non-existent until term (2017).
L-selectin acts as a "homing receptor" for lymphocytes to enter secondary lymphoid tissues via high endothelial venules. Ligands present on endothelial cells will bind to lymphocytes expressing L-selectin, slowing lymphocyte trafficking through the blood, and facilitating entry into a secondary lymphoid organ at that point. The receptor is commonly found on the cell surfaces of T cells. Naive T-lymphocytes, which have not yet encountered their specific antigen, need to enter secondary lymph nodes to encounter their antigen. Central memory T-lymphocytes, which have encountered antigen, express L-selectin to localize in secondary lymphoid organs. Here they reside ready to proliferate upon re-encountering antigen. Effector memory T-lymphocytes do not express L-selectin, as they circulate in the periphery and have immediate effector functions upon encountering antigen. High expression of L-selectin on human bone marrow progenitor cells is an early sign of cells becoming committed to lymphoid differentiation.
Neutrophils and Monocytes
Similar to its role in homing lymphocytes to secondary lymphoid tissues, L-selectin expressed on the surface of monocytes and neutrophils is essential for facilitating the first stage of adhesion to venule epithelial cells (known as the “rolling stage”). Adhesion to activated epithelial cells is a critical step in the immune response as it allows these immune cells to emigrate from the bloodstream into inflamed tissue. Prolonged rolling and transmigration of neutrophils can trigger shedding of L-selectin from the neutrophil plasma membrane. The membrane-bound fragment left behind following cleavage of L-selectin has also been suggested to play a critical role in the interstitial chemotaxis of neutrophils along a cytokine gradient. L-selectin shedding also occurs in monocytes; however, in these cells shedding is triggered only during trans-endothelial and not by earlier stages of the adhesion process. The specific shedding of L-selectin from the leading migratory fronts of transmigrating monocytes suggests that this process plays a role in facilitating the directional migration of these cells (2019).
L-selectin is also present on the surface of human embryo trophoblasts prior to implantation into the uterus. Similar to its function in lymphocytes, L-selectin acts as a receptor to facilitate adhesion of the embryo to the site of invasion on the surface epithelium of the uterine endometrium. The embryo secretes human chorionic gonadotropin (hCG), which downregulates anti-adhesion factor, MUC-1, located on the uterine epithelium at the site of invasion. Removal of MUC-1 exposes the oligosaccharide ligands of the uterine epithelium, thus allowing binding by the L-selectin receptor of the trophoblast cell, followed by embryo adhesion and invasion.
Human Immunodeficiency Virus (HIV)
L-selectin expressed on CD4 T lymphocytes has been implicated in mediating adhesion and entry of HIV. L-selectin binds gp120, one of the many glycans present on the HIV envelope. This binding allows for rolling adhesion to T cells and thus facilitates the binding of HIV to its target receptors. Infection of the cell triggers shedding of L-selectin. The loss of L-selectin likely aids in the release of new virus from the cell.
Abnormal Pregnancy and infertility
The binding of L-selectin to its ligands plays an important role in embryo implantation during human pregnancy. Deficiency epithelial expression of L-selectin ligands has been associated with infertility, while increased expression has been implicated in ectopic pregnancies
The adhesive properties of L-selectin have been shown to contribute to cancer progression. L-selectin interactions participate in trafficking of chronic lymphocytic leukemia cells to the lymph nodes where they are able to proliferate and evolve. Additionally, L-selectin interactions may play a role in metastasis.
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