Binds to Macrophage Mannose Receptor on Lymphatic Endothelium and Supports Lymphocyte Migration via Afferent Lymphatics Short Communication

L eukocyte migration from the periphery into the draining lymph nodes via the afferent lymphatics largely determines the magnitude of immune response within the node. Exit of lymphocytes from the lymph nodes via the lymphoid sinuses into efferent lymphatics also controls the recirculation potential of naive and activated lymphocytes. Furthermore, the lymphatic vasculature also presents an important route for cancer cells to metastasize. Macrophage mannose receptor (MRC) is a scavenger receptor on macrophages and mediates the uptake of mannosyl-ated glycoconjugates. It is also expressed on lymphatics and is involved in the migration of lymphocytes and melanoma cells into the draining lymph nodes. 1 As a large protein consisting of a cysteine-rich (CR)/ricin R-type lectin domain, a fibronectin type II domain, and 8 C-type lectin domains, it has the potential to interact with diverse ligands. 2 In vitro binding studies indicate that L-selectin functions as a leukocyte ligand for MRC at least in lymphoid sinuses. 3,4 Because L-selectin– negative cells also migrate in an MRC-dependent manner via the afferent lymphatics, 1 we wanted to identify additional leu-kocyte counter receptors for MRC. On the basis of the protein structure and function, we hypothesized that CD44 might interact with MRC. CD44 is a proteoglycan having ≥40 isoforms as a result of the alternative splicing and abundant posttranslational modifications. It is involved in a multitude of functions, including apoptosis, adhesion to extracellular matrix, and lymphocyte homing from the blood into the lymphoid organs. 5 The standard hematopoietic form of CD44 has glycosaminoglycan side chains, which are predominantly chondroitin-4 and-6-sulfates. In addition, the core protein incorporates sulfate directly to its other oligosaccharide components or amino acids. 6,7 The best-characterized ligand for leukocyte CD44 is hyaluronan, present on the endothelial cell surface of blood vessels, and this interaction is important in the rolling phase of leukocyte extravasation. In addition, CD44 on mature leukocytes binds to endothelial selectins, and it can induce signals activating other adhesion molecules (eg, lymphocyte function-associated antigen-1). Rationale: Macrophage mannose receptor (MRC) is one of the few molecules known to be involved in lymphocyte trafficking via the lymphatic vessels. In endothelial cells of efferent lymphatics, it binds L-selectin on lymphocytes. In afferent lymphatics, MRC mediates trafficking of both normal and malignant L-selectin–negative cells to the draining lymph nodes. Objective: This work was designed to search for additional lymphocyte ligands of MRC to elucidate how lymphocytes migrate into the draining lymph nodes. Conclusions: These …