Dendritic Cells Distinguish Individual Chemokine Signals through CCR7 and CXCR4

Ricart, Brendon G.; John, Beena; Lee, Dong Hoon; Hunter, Christopher A.; Hammer, Daniel A.

doi:10.4049/jimmunol.1002358

Cited by 133 publications

(154 citation statements)

References 55 publications

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“…Thus, the CCL19 gradient needed to be twice that of CCL21 to prevent chemotaxis towards CCL21. This result differs from that of a recent DC-chemotaxis study in 2D under flow (19), where DCs are only weakly adhesive.…”

Section: Resultscontrasting

confidence: 56%

“…However, our current understanding of DC chemotaxis is largely qualitative and limited to 2D (16)(17)(18)(19). Furthermore, while it is well established that cell migration requires different mechanisms in 3D vs. 2D (20)(21)(22)(23)(24)(25), nearly all chemotaxis studies to date have been performed in 2D or 2.5D conditions largely because of the lack of model systems in which well defined gradients can be created in 3D while evaluating cell invasion (especially because DC migration is relatively fast compared to the time scale of diffusion for gradient establishment).…”

mentioning

confidence: 99%

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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.

186

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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Section: Resultscontrasting

confidence: 56%

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.

186

184

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“…On exposure to inflammatory chemokines, cytokines or foreign antigens, DCs mature and upregulate their crucial signaling-guiding receptor CCR7 (24). In our study, exogenous i.c.…”

Section: Discussionmentioning

confidence: 92%

Ischemia–Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts

Dashkevich

Raissadati

Syrjälä

et al. 2016

American Journal of Transplantation

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Organ damage and innate immunity during heart transplantation may evoke adaptive immunity with serious consequences. Because lymphatic vessels bridge innate and adaptive immunity, they are critical in immune surveillance; however, their role in ischemia–reperfusion injury (IRI) in allotransplantation remains unknown. We investigated whether the lymphangiogenic VEGF‐C/VEGFR3 pathway during cardiac allograft IRI regulates organ damage and subsequent interplay between innate and adaptive immunity. We found that cardiac allograft IRI, within hours, increased graft VEGF‐C expression and lymphatic vessel activation in the form of increased lymphatic VEGFR3 and adhesion protein expression. Pharmacological VEGF‐C/VEGFR3 stimulation resulted in early lymphatic activation and later increase in allograft inflammation. In contrast, pharmacological VEGF‐C/VEGFR3 inhibition during cardiac allograft IRI decreased early lymphatic vessel activation with subsequent dampening of acute and chronic rejection. Genetic deletion of VEGFR3 specifically in the lymphatics of the transplanted heart recapitulated the survival effect achieved by pharmacological VEGF‐C/VEGFR3 inhibition. Our results suggest that tissue damage rapidly changes lymphatic vessel phenotype, which, in turn, may shape the interplay of innate and adaptive immunity. Importantly, VEGF‐C/VEGFR3 inhibition during solid organ transplant IRI could be used as lymphatic‐targeted immunomodulatory therapy to prevent acute and chronic rejection.

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“…[1][2][3][4] The DCs migrate to the draining lymph nodes, as a result of the up-regulation of CCR7, which renders them responsive to CCL19 and CCL21 chemokines that direct their migration to the T-cell areas of lymph nodes. 6 Finally, the mature DCs present the antigen to naive CD4 + and CD8 + T lymphocytes. The maturational status can be modulated by different stimuli.…”

Section: Introductionmentioning

confidence: 99%

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

Álvarez¹,

Amaral²,

Langellotti³

et al. 2011

Immunology

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Summary Leukotriene C4 is an important mediator in the development of inflammatory reactions and ischaemia. Previous studies have shown that leukotriene C4 is able to modulate the function of dendritic cells (DCs) and induce their chemotaxis from skin to lymph node. In this study, we decided to evaluate the modulation exerted by leukotriene C4 on DCs, depending on their status of activation. We showed for the first time that leukotriene C4 stimulates endocytosis both in immature and lipopolysaccharide (LPS) ‐activated DCs. Moreover, it suppressed the interleukin‐12p70 (IL‐12p70) release, but induces the secretion of IL‐23 by DCs activated with LPS and promotes the expansion of T helper type 17 (Th17) lymphocytes. Furthermore, blocking the release of IL‐23 reduced the percentages of CD4+ T cells producing IL‐17 in a mixed lymphocyte reaction. Ours results suggest that leukotriene C4 interferes with the complete maturation of inflammatory DCs in terms of phenotype and antigen uptake, while favouring the release of IL‐23, the main cytokine involved in the maintenance of the Th17 profile.

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Dendritic Cells Distinguish Individual Chemokine Signals through CCR7 and CXCR4

Cited by 133 publications

References 55 publications

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

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

Ischemia–Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

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