Regulation of immune cell responses by semaphorins and their receptors

Takamatsu, Hyota; Okuno, Tatsusada; Kumanogoh, Atsushi

doi:10.1038/cmi.2009.111

Cited by 90 publications

(60 citation statements)

References 93 publications

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“…The MV gp complex displayed on the MV-DC/T-cell interface essentially, yet not fully determined IS destabilization and thus, other molecules, potentially including SEMA receptors are likely to be involved also. The important role of the plexA1/NP-1 complex in regulating immune functions has been documented because their ligands determine whether they functionally support (by selfinteraction) or rather contribute to termination of (by SEMA3A interaction) the IS [22,23,44]. The importance of the ligandbinding NP-1 in the IS has been established in murine and human systems [32,45], and we now confirmed that, similar to the murine system, plexA1 is an important component of IS function (Fig.…”

Section: Discussionsupporting

confidence: 79%

“…ligands determine whether they functionally support (by selfinteraction) or rather contribute to termination of (by SEMA3A interaction) the IS [22,23,44]. The importance of the ligandbinding NP-1 in the IS has been established in murine and human systems [32,45], and we now confirmed that, similar to the murine system, plexA1 is an important component of IS function (Fig.…”

supporting

confidence: 80%

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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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Section: Discussionsupporting

confidence: 79%

supporting

confidence: 80%

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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“…These are activating receptors characterized by immunoreceptor tyrosine-based activating motifs in their cytoplasmic domain (Fc␥RIIC, Fc␣R, Fc⑀RI) or pairing with an immunoreceptor tyrosine-based activating motif-containing transmembrane adaptor proteins for signaling (Fc␥RIIIA), which trigger phagocytosis and immune complex clearance, inflammatory cytokine production, antibody-dependent cellular cytotoxicity, and respiratory burst. 43 Hypoxic up-regulation of other genes encoding Ig family members, such as BDCA3, LILRA2, and SEMA4D, 35,44,45 was also observed. These molecules modulate DC maturation, immunogenicity, cooperation with T cells, and proinflammatory cytokine production.…”

Section: Discussionmentioning

confidence: 98%

Hypoxia modulates the gene expression profile of immunoregulatory receptors in human mature dendritic cells: identification of TREM-1 as a novel hypoxic marker in vitro and in vivo

Bosco

Pierobon

Blengio

et al. 2011

Blood

112

107

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“…A case in point is semaphorin 4a (SEMA4a), which was found to have strong protective effects against beta cell lipotoxic insults, but actually promoted beta cell death under other conditions [4]. Members of the semaphorin family were originally discovered as repulsive axon guidance cues, but SEMA4a also plays important roles in the immune system, where it is expressed on the membrane of dendritic cells and interacts with T cell surface receptors to provide co-stimulation in T helper type 1 cell differentiation [20]. However, as is the case for OLFM1, SEMA4a had not previously been associated with beta cell function, which illustrates the power of non-biased efforts such that by Yang et al to identify entirely novel factors that contribute to beta cell survival.…”

Section: Gfpmentioning

confidence: 99%

Tuning to the right signal

Huising

2015

Diabetologia

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Pancreatic beta cells are clustered in islets of Langerhans together with alpha cells in an arrangement that facilitates the tight coordination of insulin and glucagon secretion at the source of their release. Other secretory cells, including somatostatin-secreting delta cells and pancreatic polypeptide cells, co-localise with alpha and beta cells in the islet and serve to modulate islet endocrine output. A multitude of non-secretory cell types, including endothelial cells, pericytes, stromal cells, glial cells and macrophages, complete the cellular make up of the islet, which is further enhanced by (para)sympathetic nerve terminals that impinge on the islets via neurotransmitters released in the islet microenvironment. While this islet architecture is relatively simple compared with the vast complexity of the central nervous system, the constellation of cell types united in the islet nevertheless provides a rich substrate for local paracrine and autocrine interactions that affect diverse aspects of islet physiology, ranging from the modulation of hormone secretion to the regulation of islet cell mass via proliferation and death. In this issue of Diabetologia (DOI: 10.1007/s00125-015-3552-5), Yang et al take the notion of rich crosstalk within the islet as their point of departure for a systematic evaluation of the beta cellprotective properties of an extensive panel of over 200 factors, with some surprising and highly interesting results, as discussed in this commentary.

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Regulation of immune cell responses by semaphorins and their receptors

Cited by 90 publications

References 93 publications

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

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

Hypoxia modulates the gene expression profile of immunoregulatory receptors in human mature dendritic cells: identification of TREM-1 as a novel hypoxic marker in vitro and in vivo

Tuning to the right signal

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