Roles of Sulfated Glycans in Lymphocyte Homing

Abstract

LYMPHOCYTE HOMINGLymphocytes are generated in primary lymphoid organs, such as the bone marrow and thymus, and migrate to the lymph nodes, Peyer's patches, and spleen, known as secondary lymphoid organs, where the immune responses occur. Lymphocytes that migrate to the lymph nodes and Peyer's patches emigrate through the efferent lymph, unless they encounter their cognate antigens. Lymphocytes that emigrate through the lymph return to the bloodstream through the thoracic duct, through which lymph fluid drains into the blood. Lymphocytes that return to the blood migrate again into the secondary lymphoid organs. This circulatory process is called lymphocyte recirculation or lymphocyte homing. Antigens that enter the body from peripheral tissues such as the skin accumulate in the lymph nodes. Antigens in the blood are collected in the spleen. Those in food are taken up by M cells residing in the mucosal intestinal epithelial barrier and accumulate in the Peyer's patches. Thus, the secondary lymphoid organs are the sites where foreign antigens accumulate and immune responses primarily occur. The homing of lymphocytes into secondary lymphoid organs through the blood and lymph circulation raises the likelihood that lymphocytes will encounter antigens. In other words, lymphocyte homing is important for the immune system to recognize foreign antigens efficiently.Lymphocytes migrate into the parenchyma of lymph nodes through specialized blood vessels called high endothelial venules (HEV). HEV have a characteristic cuboidal morphology and a prominent Golgi complex where unique sulfated glycans are synthesized, as discussed later. Lymphocyte migration is achieved by a series of interactions between lymphocytes and HEV 1) ( Fig. 1): (i) the rolling of lymphocytes, which is mediated by L-selectin on the lymphocytes and sulfated glycans on the HEV; (ii) activation of the lymphocytes by chemokines presented on the surface of the HEV by heparan sulfate, a glycosaminoglycan; (iii) firm attachment of the lymphocytes through the interaction between b2 integrins on the lymphocytes and intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1) on the HEV; and (iv) transmigration. HOMING RECEPTOR L-SELECTINThe homing receptor L-selectin (LECAM-1, CD62L, LAM-1) was first identified as an antigen recognized by the monoclonal antibody (mAb) MEL-14, which blocks the binding of lymphocytes to HEV in vitro and in vivo. L-selectin is an adhesion molecule that recognizes carbohydrates through a lectin-like domain in its N-terminus, through which it mediates the initial tethering and rolling of lymphocytes on the surface of HEV. L-selectin is localized to the tips of microvilli, 2) which is advantageous for the initial tethering to HEV-borne carbohydrate ligands. To date, several kinds of glycoprotein ligands for L-selectin have been identified (see below).L-selectin is expressed not only on lymphocytes, but also on other types of leukocytes, such as neutrophils and monocytes. L-selectin is involved in the infilt...

Regulation of Glycan Structures in Animal Tissues

“…Sulfation reactions leading to the synthesis of sialyl 6-sulfo Lewis x structures are catalyzed by sulfotransferases associated with high endothelial venules, where they create ligands for interaction with L-selectin during lymphocyte homing to lymph nodes (91,92). The sulfated structures are generated on the termini of core 1 and core 2 sialomucins by the sulfotransferases GlcNAc6ST-1 (Chst2) and GlcNAc6ST-2 (Chst4) (92).…”

Membrane cholesterol modulates the hyaluronan-binding ability of CD44 in T lymphocytes and controls rolling under shear flow

“…This process begins with the establishment of transient adhesive interactions that result in the rolling of lymphocytes along the endothelium under blood flow. This rolling adhesion is prerequisite for the subsequent firm adhesion of lymphocytes to the endothelium and transmigration across blood vessels, and the roles of selectins and their sulfated glycan ligands in rolling adhesion have been well investigated (Rosen, 2004;Kawashima et al, 2005;Kawashima, 2006). The rolling is also mediated by the interactions between the transmembrane adhesion receptor CD44 and its glycan ligand: CD44 on T cells mediates the rolling of T cells on the extracellular matrix component hyaluronan (HA), a linear glycosaminoglycan composed of D-glucuronic acid and N-acetyl-D-glucosamine repeats, in vitro (DeGrendele et al, 1996;Clark et al, 1996).…”

Norepinephrine Promotes the β1-Integrin–Mediated Adhesion of MDA-MB-231 Cells to Vascular Endothelium by the Induction of a GROα Release

“…With our in vitro flowthrough adhesion assay, we show that GROa, and to a lesser extent, IL-8, can promote the adhesion of CXCR1/ CXCR2-positive tumor cells to endothelium. Chemokines are released by endothelial cells in response to certain stimuli and then become bound on the apical side of the endothelial cell layer by glycosaminoglycans (34,35). By this action, they are presented to rolling cells leading to the rapid activation of integrins (17,36).…”