Homeostatic Lymphoid Chemokines Synergize with Adhesion Ligands to Trigger T and B Lymphocyte Chemokinesis

Stachowiak, Agnieszka N.; Wang, Yana; Huang, Yen‐Chang; Irvine, Darrell J.

doi:10.4049/jimmunol.177.4.2340

Cited by 70 publications

(83 citation statements)

References 52 publications

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“…It is possible that signaling through SLC binding to CCR7 requires synergism with signaling events from other pathways to induce an optimal response. Indeed, previous reports have demonstrated that SLC can synergize with other adhesion molecules such as ICAM-1 and VCAM-1 to promote chemokinesis of lymphocytes during in vitro assays (57). Therefore, the finding that L-selectin-mediated enhancement in chemotaxis was specific for SLC and not ELC may be due to the inherent differences in intracellular signaling events triggered by the binding of these two chemokines to CCR7.…”

Section: Discussionmentioning

confidence: 51%

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

Subramanian

Grailer

Ohlrich

et al. 2012

The Journal of Immunology

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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.

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Section: Discussionmentioning

confidence: 51%

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

Subramanian

Grailer

Ohlrich

et al. 2012

The Journal of Immunology

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“…Because CCR7 signaling can increase motility in T cells (15) and in some cases DCs in 2D culture (34,35), we next examined the influence of CCL19 and CCL21 on DC motility in a 3D environment both in terms of activating cells to be motile as well as affecting their average (random) speed. We found that in 3D, chemokinetic effects on DCs were relatively small (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, the positively charged C terminus of CCL21 gives it strong binding affinity to a wide range of proteoglycans [as well as type IV collagen (10)], unlike CCL19 (11)(12)(13). Additionally, matrix-bound CCL21 can activate DC and T cell adhesion to adhesion ligands like ICAM-1 (14,15). This study addresses the question of how DCs respond to gradients of CCR7 ligands in 3D environments-in particular, whether they differentiate between soluble vs. matrix-bound signals, and the relative importance of gradient steepness vs. average concentration.…”

mentioning

confidence: 99%

Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19

Haessler

Pisano

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

184

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Dendritic cell (DC) homing to the lymphatics and positioning within the lymph node is important for adaptive immunity, and is regulated by gradients of CCL19 and CCL21, ligands for CCR7. Despite the importance of DC chemotaxis, it is not well understood how DCs interpret gradients of these chemokines in a complex 3D microenvironment. Here, we use a microfluidic device that allows rapid establishment of stable gradients in 3D matrices to show that DC chemotaxis in 3D can respond to CCR7 ligand gradients as small as 0.4%, which helps explain how DCs sense lymphatic vessels in an environment where broadcast distance for chemokine diffusion is hindered by convective flows into the vessel. Interestingly, DCs displayed similar sensitivities to both chemokines at small gradients (≤60 nM∕mm), but migrated more efficiently towards higher gradients of CCL21, which unlike CCL19 binds strongly to matrix proteoglycans and signals without the need for internalization. Furthermore, cells preferentially migrated towards CCL21 when exposed to equal and opposite gradients of CCL21 and CCL19 simultaneously, even when matrix-binding of CCL21 was prevented. Although these ligands have similar binding affinity to CCR7, our results demonstrate that, in a 3D environment, CCL21 is a more potent directional cue for DC migration than CCL19. These findings provide new quantitative insight into DC chemotaxis in a physiological 3D environment and suggest how CCL19 and CCL21 may signal differently to fine-tune DC homing and positioning within the lymphatic system. These results also have broad relevance to other systems of cell chemotaxis, which remain poorly understood in the 3D context.D endritic cells (DCs) are considered the most potent and professional antigen-presenting cells. DCs are positioned throughout the periphery, and when activated, migrate to lymphatic vessels and into lymph nodes, where they can direct antigen-specific Tcell responses. Upon activation or maturation, DCs upregulate the C-C chemokine-receptor CCR7, which allows them to sense and home towards CCR7 ligand-secreting lymphatic vessels and lymph nodes (1). The two known ligands for CCR7 are the C-C chemokines CCL21 and CCL19 (2); both are secreted by stromal cells in the lymph node paracortex to properly position DCs with CCR7 þ naïve T cells for their activation. CCL21, but not CCL19, is also expressed by the endothelium of lymphatic vessels in the periphery (1). Thus, CCR7-mediated chemotaxis is critical for DC homing to, and positioning within, lymph nodes and for T cell activation there (3).CCL19 and CCL21 function as directional signals presumably by virtue of concentration gradients (∇C) that guide DCs towards areas of increasing concentrations. Interestingly, CCL19 and CCL21 have similar binding affinities for CCR7 (4-6) and similar chemotactic potential for DCs and T cells under 2D conditions (7,8), but differ in their internalization (8, 9) as well as their binding affinity to extracellular matrix (ECM) proteoglycans. Specifically, the positively charged C t...

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“…The efficacy of CCR7 ligands in promoting chemokinesis (this study and Refs. 26,32) suggests that CCR7 may be especially adapted for promoting and maintaining cell motility for prolonged periods. We speculate that CXCR5 is similarly adapted for promoting prolonged B cell motility within lymphoid follicles.…”

Section: Discussionmentioning

confidence: 99%

CC Chemokine Receptor 7 Contributes to Gi-Dependent T Cell Motility in the Lymph Node

Okada

Cyster

2007

The Journal of Immunology

173

169

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Naive T cells migrate extensively within lymph node (LN) T zones to scan for Ag-bearing dendritic cells. However, the extracellular signals controlling T cell motility in LNs are not well defined. In this study, by real-time imaging of LNs, we show that the inhibition of Gi signaling in T cells severely impairs their migration. The chemokine CCL21, a ligand of CCR7, strongly induces chemokinesis in vitro, and T cell motility in LNs from CCR7 ligand-deficient plt/plt mice was reduced. CCR7-deficient T cells in wild-type LNs showed a similar reduction in motility, and antagonism of CXCR4 function did not further decrease their motility. The effect of CCR7 or CCR7-ligand deficiency could account for ∼40% of the Gi-dependent motility. These results reveal a role for CCR7 in promoting T cell migration within lymphoid organ T zones, and they suggest the additional involvement of novel Gi-coupled receptors in promoting T cell motility at these sites.

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Homeostatic Lymphoid Chemokines Synergize with Adhesion Ligands to Trigger T and B Lymphocyte Chemokinesis

Cited by 70 publications

References 52 publications

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

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

Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19

CC Chemokine Receptor 7 Contributes to Gi-Dependent T Cell Motility in the Lymph Node

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