Interstitial Dendritic Cell Guidance by Haptotactic Chemokine Gradients

Weber, Michele; Hauschild, Robert; Schwarz, Jan; Moussion, Christine; Vries, Ingrid de; Legler, Daniel F.; Luther, Sanjiv A.; Bollenbach, Tobias; Sixt, Michael

doi:10.1126/science.1228456

Cited by 466 publications

(608 citation statements)

References 30 publications

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“…Although it is intuitive to assume that B cells would follow a chemotactic gradient from their site of entry in the T-cell zone toward adjacent B-cell follicles, as recently observed during dendritic cell migration to lymphatic vessels, 35,36 we did not find evidence for directed motility inside lymphoid tissue. While we cannot exclude a subtle follicle-directed B-cell taxis that is undetectable due to the confined observation volume and duration, 37 B cells in close proximity to follicles typically turned back into the T-cell area.…”

Section: Discussioncontrasting

confidence: 34%

Naive B-cell trafficking is shaped by local chemokine availability and LFA-1–independent stromal interactions

Coelho

Natale

Soriano

et al. 2013

Blood

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Key Points• CXCR5, but not CXCR4 or CCR7, acts with LFA-1 to mediate random B-cell migration in the T-cell area and B-cell follicles.• In contrast, stromal guidance during B-cell migration is LFA-1 independent and CXCR5 independent.It is not known how naive B cells compute divergent chemoattractant signals of the T-cell area and B-cell follicles during in vivo migration. Here, we used two-photon microscopy of peripheral lymph nodes (PLNs) to analyze the prototype G-protein-coupled receptors (GPCRs) CXCR4, CXCR5, and CCR7 during B-cell migration, as well as the integrin LFA-1 for stromal guidance. CXCR4 and CCR7 did not influence parenchymal B-cell motility and distribution, despite their role during B-cell arrest in venules. In contrast, CXCR5 played a nonredundant role in B-cell motility in follicles and in the T-cell area. B-cell migration in the T-cell area followed a random guided walk model, arguing against directed migration in vivo. LFA-1, but not a4 integrins, contributed to B-cell motility in PLNs. However, stromal network guidance was LFA-1 independent, uncoupling integrin-dependent migration from stromal attachment. Finally, we observed that despite a 20-fold reduction of chemokine expression in virus-challenged PLNs, CXCR5 remained essential for B-cell screening of antigen-presenting cells. Our data provide an overview of the contribution of prototype GPCRs and integrins during naive B-cell migration and shed light on the local chemokine availability that these cells compute. (Blood. 2013;121(20):4101-4109)

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Section: Discussioncontrasting

confidence: 34%

Naive B-cell trafficking is shaped by local chemokine availability and LFA-1–independent stromal interactions

Coelho

Natale

Soriano

et al. 2013

Blood

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“…The mechanism by which CCR7 mediates accumulation of migratory DCs in draining LN involves guidance of the DCs within the perilymphatic interstitium along gradients of the CCR7 ligand CCL21 that is produced by the lymphatic capillary endothelial cells (48). Although we could not detect CCR7 on SI LP DCs directly ex vivo, the moderate difference observed between WT and MyD88-deficient SI LP-derived CD103 + DCs in the MLN indicates that MyD88 is involved in regulating CCR7 expression in these cells also in the steady state.…”

Section: Discussionmentioning

confidence: 99%

MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota

Hägerbrand

Westlund

Agace

et al. 2015

The Journal of Immunology

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Intestinal homeostasis and induction of systemic tolerance to fed Ags (i.e., oral tolerance) rely on the steady-state migration of small intestinal lamina propria dendritic cells (DCs) into draining mesenteric lymph nodes (MLN). The majority of these migratory DCs express the α integrin chain CD103, and in this study we demonstrate that the steady-state mobilization of CD103+ DCs into the MLN is in part governed by the IL-1R family/TLR signaling adaptor molecule MyD88. Similar to mice with complete MyD88 deficiency, specific deletion of MyD88 in DCs resulted in a 50–60% reduction in short-term accumulation of both CD103+CD11b+ and CD103+CD11b− DCs in the MLN. DC migration was independent of caspase-1, which is responsible for the inflammasome-dependent proteolytic activation of IL-1 cytokine family members, and was not affected by treatment with broad-spectrum antibiotics. Consistent with the latter finding, the proportion and phenotypic composition of DCs were similar in mesenteric lymph from germ-free and conventionally housed mice. Although TNF-α was required for CD103+ DC migration to the MLN after oral administration of the TLR7 agonist R848, it was not required for the steady-state migration of these cells. Similarly, TLR signaling through the adaptor molecule Toll/IL-1R domain-containing adapter inducing IFN-β and downstream production of type I IFN were not required for steady-state CD103+ DC migration. Taken together, our results demonstrate that MyD88 signaling in DCs, independently of the microbiota and TNF-α, is required for optimal steady-state migration of small intestinal lamina propria CD103+ DCs into the MLN.

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“…Although this concept has been established based on in vitro assays, it is widely accepted. Two recent studies now provide direct evidence from tissues that gradients of the chemokines CXCL8 and CCL21 for attracting leukocytes are established by glycan binding [3,4]. Interestingly, some chemokines such as CCL2 are additionally stored locally in vesicles resembling type 2 granules that are docked on actin fibers just beneath the plasma membrane of endothelial cells, and hence are not exposed at the surface and not visible [5].…”

Section: Establishing and Shaping Chemotactic Gradientsmentioning

confidence: 99%

“…The importance of CME for focal adhesion disassembly is highlighted by the fact that depletion of dynamin2 blocks b1 integrin internalization leading to impaired focal adhesion disassembly and consequently to defects in cell migration [86]. CME depends on phosphatidylinositol (4,5)bisphosphate [PI(4,5)P 2 ] which is generated by the enzyme PIPK1b and contributes to the recruitment of endocytic proteins like AP-2. Consistently, depletion of PIPK1b likewise decreased internalization of active b1 integrin, focal adhesion turnover and migration due to the impaired recruitment of the endocytic machinery to focal adhesion sites [87].…”

Section: Focal Adhesion Disassemblymentioning

confidence: 99%

On the move: endocytic trafficking in cell migration

Maritzen

Schachtner

Legler

2015

Cell. Mol. Life Sci.

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Directed cell migration is a fundamental process underlying diverse physiological and pathophysiological phenomena ranging from wound healing and induction of immune responses to cancer metastasis. Recent advances reveal that endocytic trafficking contributes to cell migration in multiple ways. (1) At the level of chemokines and chemokine receptors: internalization of chemokines by scavenger receptors is essential for shaping chemotactic gradients in tissue, whereas endocytosis of chemokine receptors and their subsequent recycling is key for maintaining a high responsiveness of migrating cells. (2) At the level of integrin trafficking and focal adhesion dynamics: endosomal pathways do not only modulate adhesion by delivering integrins to their site of action, but also by supplying factors for focal adhesion disassembly. (3) At the level of extracellular matrix reorganization: endosomal transport contributes to tumor cell migration not only by targeting integrins to invadosomes but also by delivering membrane type 1 matrix metalloprotease to the leading edge facilitating proteolysis-dependent chemotaxis. Consequently, numerous endocytic and endosomal factors have been shown to modulate cell migration. In fact key modulators of endocytic trafficking turn out to be also key regulators of cell migration. This review will highlight the recent progress in unraveling the contribution of cellular trafficking pathways to cell migration.

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Interstitial Dendritic Cell Guidance by Haptotactic Chemokine Gradients

Cited by 466 publications

References 30 publications

Naive B-cell trafficking is shaped by local chemokine availability and LFA-1–independent stromal interactions

Naive B-cell trafficking is shaped by local chemokine availability and LFA-1–independent stromal interactions

MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota

On the move: endocytic trafficking in cell migration

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