Semaphorins guide the entry of dendritic cells into the lymphatics by activating myosin II

Takamatsu, Hyota; Takegahara, Noriko; Nakagawa, Yukinobu; Tomura, Michio; Taniguchi, Masahiko; Friedel, Roland H.; Rayburn, Helen; Tessier‐Lavigne, Marc; Yoshida, Yutaka; Okuno, Tatsusada; Mizui, Masayuki; Kang, Sujin; Nojima, Satoshi; Tsujimura, Tohru; Nakatsuji, Yuji; Katayama, Ichiro; Toyofuku, Toshihiko; Kikutani, Hitoshi; Kumanogoh, Atsushi

doi:10.1038/ni.1885

Cited by 188 publications

(166 citation statements)

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“…22,40 Furthermore, it was recently reported that actomyosin-mediated nuclear contraction, induced by LEC-expressed semaphorin 3A, was important for DC entry into LVs. 10 Given these findings and the fact that ROCK is important for DC migration through dense collagen meshworks in vitro, 2 it is rather probable that ROCK is required for DC transmigration through the perilymphatic BM and subsequent entry into lymphatic capillaries. Interestingly, when imaging DCs in Y27632-treated mice we observed one DC that seemed to be arrested in the transmigration process (supplemental Video 9).…”

Section: Rock In DC Migration and Intralymphaticmentioning

confidence: 99%

“…6,7 More recently, also other LEC-expressed molecules that mediate DC migration via LVs to dLNs have been identified. [8][9][10][11] Notably, ICAM-1 and VCAM-1, which are up-regulated in LVs during inflammation, 8,12 have been implicated in this process. 8 Intriguingly, experiments performed with pan-integrin knockout DCs revealed that DC migration to dLNs in steady-state was integrin-independent.…”

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confidence: 99%

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Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation

Nitschké

Aebischer

Abadier

et al. 2012

Blood

135

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Dendritic cell (DC) migration via lymphatic vessels to draining lymph nodes (dLNs) is crucial for the initiation of adaptive immunity. We imaged this process by intravital microscopy (IVM) in the ear skin of transgenic mice bearing redfluorescent vasculature and yellowfluorescent DCs. DCs within lymphatic capillaries were rarely transported by flow, but actively migrated within lymphatics and were significantly faster than in the interstitium. Pharmacologic blockade of the Rho-associated protein kinase (ROCK), which mediates nuclear contraction and de-adhesion from integrin ligands, significantly reduced DC migration from skin to dLNs in steady-state. IVM revealed that ROCK blockade strongly reduced the velocity of interstitial DC migration, but only marginally affected intralymphatic DC migration. By contrast, during tissue inflammation, ROCK blockade profoundly decreased both interstitial and intralymphatic DC migration. Inhibition of intralymphatic migration was paralleled by a strong up-regulation of ICAM-1 in lymphatic endothelium, suggesting that during inflammation ROCK mediates de-adhesion of DC-expressed integrins from lymphatic-expressed ICAM-1. Flow chamber assays confirmed an involvement of lymphatic-expressed ICAM-1 and DC-expressed ROCK in DC crawling on lymphatic endothelium. Overall, our findings further define the role of ROCK in DC migration to dLNs and reveal a differential requirement for ROCK in intralymphatic DC crawling during steadystate and inflammation. (Blood. 2012; 120(11):2249-2258) IntroductionDendritic cells (DCs) are important in the initiation of adaptive immune responses. In peripheral tissues, such as the skin, DCs take up antigen, mature, and migrate via lymphatic vessels (LVs) to draining lymph nodes (dLNs), where they present antigen to resting T cells. Although this migration pattern has been known for more than 20 years, 1 DC migration into LVs is only now starting to be unraveled at the cellular level using live imaging technologies. [2][3][4] Before transmigrating across the lymphatic endothelium, DCs first need to squeeze through preformed, narrow pores present in the lymphatic basement membrane (BM). 3 DC entry into LVs is thought to occur at the level of primary lymphatic capillaries, which feature discontinuous cell junctions with "button"-like accumulations of cell adhesion molecules. 5 At the sites of such buttons, lymphatic endothelial cells (LECs) partially overlap and generate open flaps, through which leukocytes enter into lymphatics. 3,5 The most prominent mediator of DC migration into afferent lymphatics is CCL21, a chemokine constitutively expressed in LVs. 6,7 More recently, also other LEC-expressed molecules that mediate DC migration via LVs to dLNs have been identified. [8][9][10][11] Notably, ICAM-1 and VCAM-1, which are up-regulated in LVs during inflammation, 8,12 have been implicated in this process. 8 Intriguingly, experiments performed with pan-integrin knockout DCs revealed that DC migration to dLNs in steady-state was integrin-independent. 2 This ...

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Section: Rock In DC Migration and Intralymphaticmentioning

confidence: 99%

mentioning

confidence: 99%

Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation

Nitschké

Aebischer

Abadier

et al. 2012

Blood

135

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“…Semaphorins consist of a family of soluble and transmembrane proteins, originally defined as axonal-guidance factors (7) that also induce cytoskeletal changes in immune, endothelial, and tumor cells and guide their migration (8)(9)(10) in the TME. For example, associations of Sema3a and Neuropilin-1 have been reported to regulate movement of tumor-associated macrophages (TAM) in hypoxic regions (11).…”

Section: Introductionmentioning

confidence: 99%

Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies

Evans

Jonason

Bussler

et al. 2015

Cancer Immunology Research

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Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 (PLXNB1) are broadly expressed in murine and human tumors, and their expression has been shown to correlate with invasive disease in several human tumors. SEMA4D normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the setting of cancer, SEMA4D-PLXNB1 interactions have been reported to affect vascular stabilization and transactivation of ERBB2, but effects on immune-cell trafficking in the tumor microenvironment (TME) have not been investigated. We describe a novel immunomodulatory function of SEMA4D, whereby strong expression of SEMA4D at the invasive margins of actively growing tumors influences the infiltration and distribution of leukocytes in the TME. Antibody neutralization of SEMA4D disrupts this gradient of expression, enhances recruitment of activated monocytes and lymphocytes into the tumor, and shifts the balance of cells and cytokines toward a proinflammatory and antitumor milieu within the TME. This orchestrated change in the tumor architecture was associated with durable tumor rejection in murine Colon26 and ERBB2 þ mammary carcinoma models. The immunomodulatory activity of anti-SEMA4D antibody can be enhanced by combination with other immunotherapies, including immune checkpoint inhibition and chemotherapy. Strikingly, the combination of anti-SEMA4D antibody with antibody to CTLA-4 acts synergistically to promote complete tumor rejection and survival. Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the TME and inhibit tumor progression. Cancer Immunol Res; 3(6); 689-701. Ó2015 AACR.

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“…Thus, plexinA1 (plexA1) and NP-1 were implicated in DC migration through endothelial layers and lymphatic entry [29], yet also in T-cell activation by murine or human DC [30][31][32], though neither their co-segregation at the IS nor their ligands there clearly identified. In contrast, the plexA1/NP-1 complex relays repulsive signals when exposed to soluble SEMA3A thereby causing loss of thymocyte adhesion, impairing actin cytoskeletal reorganization and activation of essential components of TCR signalling, or controlling Fas-mediated apoptosis [33][34][35][36][37].…”

Section: Introductionmentioning

confidence: 99%

Measles virus modulates dendritic cell/T‐cell communication at the level of plexinA1/neuropilin‐1 recruitment and activity

et al. 2010

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Measles virus (MV)-infected DC fail to promote T-cell expansion, and this could explain important aspects of measles immunosuppression. The efficiency of the immune synapse (IS) is determined by the formation of stable, stimulatory conjugates involving a spatially and timely controlled architecture. PlexinA1 (plexA1) and its co-receptor neuropilin (NP-1) have been implicated in IS efficiency, while their repulsive ligand, SEMA3A, likely acts in terminating T-cell activation. Conjugates involving MV-infected DC and T cells are unstable and not stimulatory, and thus we addressed the potential role of plexA1/NP-1 and semaphorins (SEMAs) in this system. MV does not grossly affect expression levels of plexA1/NP-1 on T cells or DC, yet prevents their recruitment towards stimulatory interfaces. Moreover, MV infection promoted early release of SEMA3A from DC, which caused loss of actin based protrusions on T cells as did the plexA4 ligand SEMA6A. SEMA3A/6A differentially modulated chemokinetic migration of T cells and conjugation with allogeneic DC. Thus, MV targets SEMA receptor function both at the level of IS recruitment, and by promoting a timely inappropriate release of their repulsive ligand, SEMA3A. To the best of our knowledge, this is the first example of viral targeting of SEMA receptor function in the IS.Keywords: Actin dynamics . DC . Measles virus . Semaphorin receptor IntroductionModulation of myeloid DC functions has been attributed an important role in viral immunosuppression, and for many systems analyzed this is reflected by the inability of infected DC to promote allogeneic T-cell expansion [1][2][3]. There are so far few examples relating this phenomenon to alterations of immune synapse (IS) stability, and these include, in addition to HIV and RSV, measles virus (MV) [4,5]. For the latter, infection of CD11c 1 DC in vivo has been directly documented and this supports the notion of CD11c 1 DC being the Trojan horses in viral transport to secondary lymphatic tissues [6][7][8]. DC mobilization from peripheral tissues relies on pattern recognition receptor signalling to promote DC maturation. Accordingly, MV acts as DC-SIGN and TLR2 agonist [7,9] and induces phenotypic maturation (including upregulation of MHC and co-stimulatory molecules and cytokine release), morphodynamic changes and enhanced motility of infected DC on fibronectin (FN) supports [10]. In contrast, CCR5/CCR7 switching, MHCII upregulation, and IL-12 production are less efficiently induced by MV as compared to other maturation stimuli [11,12]. These differences do, however, not explain the inability of MV-infected DC (MV-DC) to promote T-cell expansion in vitro [12][13][14]. Rather, ligation of an as yet unknown surface receptor by the MV glycoprotein (gp) complex (displayed on the surface of MV-DC) interferes with TCR-stimulated activation of the phosphatidylinositol-3(PI3)/Akt kinase pathway. This efficiently abrogates activation of downstream effectors essential for actin cytoskeletal reorganization and cell cycle entry (reviewed in [1...

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Semaphorins guide the entry of dendritic cells into the lymphatics by activating myosin II

Cited by 188 publications

References 50 publications

Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation

Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation

Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies

Measles virus modulates dendritic cell/T‐cell communication at the level of plexinA1/neuropilin‐1 recruitment and activity

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