Abstract
The molecular mechanisms regulating lymphocyte homing into lymph nodes are only partly understood. Here, we report that B cell-specific deletion of the X-linked gene, Cosmc, and the consequent decrease of protein O-glycosylation, induces developmental blocks of mouse B cells. After transfer into wild-type recipient, Cosmc-null B cells fail to home to lymph nodes as well as non-lymphoid organs. Enzymatic desialylation of wild-type B cells blocks their migration into lymph nodes, indicating a requirement of sialylated O-glycans for proper trafficking. Mechanistically, Cosmc-deficient B cells have normal rolling and firm arrest on high endothelium venules (HEV), thereby attributing their inefficient trafficking to alterations in the subsequent transendothelial migration step. Finally, Cosmc-null B cells have defective chemokine signaling responses. Our results thus demonstrate that Cosmc and its effects on O-glycosylation are important for controlling B cell homing.
Highlights
The molecular mechanisms regulating lymphocyte homing into lymph nodes are only partly understood
Subsequent chemokine signaling through G protein-coupled receptors, e.g. CCR7 and its ligands CCL19 and CCL21, activate lymphocyte integrins, leading to firm arrest, and the diapedesis of the adherent cells into the lymph node[7]
Multiple factors have been reported in mediating lymphocyte homing to lymphoid organs[1,2,3], yet little is known about the role of O-glycans in B cell homing
Summary
The molecular mechanisms regulating lymphocyte homing into lymph nodes are only partly understood. Naïve lymphocytes enter lymph nodes through a complex and partly understood process that begins with a series of molecular interactions requiring glycans on endothelial cells of lymph nodes that are recognized by L-selectin on lymphocytes[1,2,3]. Subsequent chemokine signaling through G protein-coupled receptors, e.g. CCR7 and its ligands CCL19 and CCL21, activate lymphocyte integrins, leading to firm arrest, and the diapedesis of the adherent cells into the lymph node[7]. It is not clear, whether the glycans on the lymphocytes themselves are important in homing. Conditional deletion of Cosmc in hematopoietic and endothelial cells results in severe pathology that leads to embryonic death; interestingly, surviving mice suffer macrothrombocytopenia and perinatal hemorrhage and die within a few months[20]
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