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Immunosurveillance requires the coordinated regulation of chemokines and adhesion molecules to guide immune cell migration. However, the critical molecule for governing the high trafficking capability of immune cells is not clear. Here we show that the effector molecule RAPL is indispensable in the integrin-mediated adhesion and migration of lymphocytes and dendritic cells. RAPL deficiency caused defective chemokine-triggered lymphocyte adhesion and migration to secondary lymphoid organs, resulting in atrophic lymphoid follicles and deficient marginal zone B cells, concomitant with increased immature B cells in the blood. Furthermore, splenic dendritic cells were diminished and defective in adhesion. After being activated with inflammatory stimuli, skin and splenic dendritic cells failed to migrate into either the draining lymph nodes or the white pulp of the spleen. Thus, RAPL is a crucial immune cell trafficking regulator essential for immunosurveillance.

Lymphocyte homing is initiated by the binding of L-selectin on lymphocytes to its ligands on high endothelial venules (HEV). Sialyl 6-sulfo Lewis X is a major capping group of L-selectin ligands. N-Acetylglucosamine (GlcNAc) 6-sulfation is essential for the ligand activity, and is catalyzed by GlcNAc 6-O-sulfotransferases (GlcNAc6STs) of which GlcNAc6ST-1 and GlcNAc6ST-2 are expressed in HEV. Here, we report that mice deficient in GlcNAc6ST-1 were impaired in the elaboration of sialyl 6-sulfo Lewis X in HEV and that an epitope of L-selectin ligands recognized by the MECA-79 anti-body was greatly reduced or abolished in the abluminal aspect of HEV. Lymphocyte homing to peripheral lymph nodes, mesenteric lymph nodes, and Peyer's patches was significantly reduced in GlcNAc6ST-1 null mice. These results demonstrate that GlcNAc6ST-1 is involved in lymphocyte homing in vivo, and indicate that GlcNAc6ST-1 and -2 play complementary roles. The importance of GlcNAc6ST-1 is particularly high-lighted by its involvement in lymphocyte homing to Peyer's patches where GlcNAc6ST-2 expression is undetectable.

The gene Bcl11b, which encodes zinc finger proteins, and its paralog, Bcl11a, are associated with immune-system malignancies. We have generated Bcl11b-deficient mice that show a block at the CD4[sup -]CD8[sup -] double-negative stage of thymocyte development without any impairment in cells of B- or γδ T cell lineages. The Bcl11b[sup -/-] thymocytes showed unsuccessful recombination of V[sub β] to D[sub β] and lacked the pre-T cell receptor (TCR) complex on the cell surface, owing to the absence of Tcrb mRNA expression. In addition, we saw profound apoptosis in the thymus of neonatal Bcl11b[sup -/-] mice. These results suggest that Bcl11b is a key regulator of both differentiation and survival during thymocyte development. [ABSTRACT FROM AUTHOR]