Signaling through L-Selectin Mediates Enhanced Chemotaxis of Lymphocyte Subsets to Secondary Lymphoid Tissue Chemokine

Abstract

L-selectin functions as an important adhesion molecule that mediates tethering and rolling of lymphocytes by binding to high endothelial venule (HEV)-expressed ligands during recirculation. Subsequent lymphocyte arrest and transmigration require activation through binding of HEV-decorated homeostatic chemokines such as secondary lymphoid tissue chemokine (SLC; CCL21) to its counterreceptor, CCR7. Importantly, L-selectin also functions as a signaling molecule. In this study, signaling induced by ligation of L-selectin using mAb or endothelial cell-expressed ligand significantly enhanced the chemotaxis of murine T cells and B cells to SLC but not to other homeostatic chemokines. Consistent with the expression levels of L-selectin in different lymphocyte subsets, L-selectin–mediated enhancement of chemotaxis to SLC was observed for all naive lymphocytes and effector/memory CD8+ T cells, whereas only a subpopulation of effector/memory CD4+ T cells responded. During in vivo mesenteric lymph node migration assays, the absence of L-selectin on lymphocytes significantly attenuated both their ability to migrate out of the HEV and their chemotaxis away from the vessel wall. Notably, ligation of L-selectin and/or CCR7 did not result in increased CCR7 expression levels, internalization, or re-expression. Pharmacologic inhibitor studies showed that L-selectin–mediated enhanced chemotaxis to SLC required intact intracellular kinase function. Furthermore, treatment of lymphocytes with the spleen tyrosine kinase family inhibitor piceatannol reduced their ability to migrate across the HEV in peripheral lymph nodes. Therefore, these results suggest that “cross-talk” in the signaling pathways initiated by L-selectin and CCR7 provides a novel mechanism for functional synergy between these two molecules during lymphocyte migration.

Integrated signaling in developing lymphocytes

“…In this regard, RAG DSBs and the pre-BCR regulate pathways to suppress the proliferative response to IL-7 and likely promote pre-B cell residence in bone marrow niches devoid of IL-7 (Fig. 1) 69,70,73,74 CD69 mediates downregulation of the S1P1 receptor, which binds to sphingosine-1-phosphate (S1P) and promotes egress of lymphocytes out of the thymus and other secondary lymphoid organs. 71,72 The S1P1 receptor is also required to promote the migration of newly generated B cells from the bone marrow.…”

A Haptotaxis Assay for Leukocytes Based on Surface-Bound Chemokine Gradients

“…The presented model system of neutrophils responding to CXCL8 is only one example of the wide field of chemokines guiding the migration of immune cells. Because chemokines are not the only determinant of immune cell migration, the role of other chemoattractants like complement factor 5a (68), inflammatory cytokines such as TNF (69), growth factors like CSF-1 (68), or modulating factors such as adhesion molecules like selectins (70) or integrins (64) could be investigated with this system. The directed migration of cells is involved in inflammation, development of the immune system, survival strategies of pathogens, and allergic reactions.…”

Is the Spleen Really Important?

“…On the other hand, CCL19 and CCL21 are fundamental for the entry of T cells into the spleen. Some selectins are also important; L-selectine, for example, is required for the migration of naïve lymphocytes into the organ [4]. The correct formation of the spleen anatomy is critical for the establishment of interactions between APC and effectors cells leading to fully mature immunological responses.…”