Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function

Catalano, Alfonso; Caprari, Paola; Moretti, Simona; Faronato, Monica; Tamagnone, Luca; Procopio, Antonio Domenico

doi:10.1182/blood-2005-06-2445

Cited by 145 publications

(145 citation statements)

References 34 publications

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“…In the immune system, we and others have shown that Nrp-1 is involved in the priming of T cells by DC [7] and in the regulation of the immunological synapse and response [8,9]. More recently, Sarris et al have extended our findings by demonstrating that high expression of Nrp-1 on Treg cells promoted their prolonged interaction with immature DC [10].…”

Section: Introductionsupporting

confidence: 77%

Neuropilin‐1 is not a marker of human Foxp3⁺ Treg

et al. 2009

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Treg are immune cells that play a critical role in the regulation of the immune response. Although the transcription factor Foxp3 is widely accepted as the standard marker of Treg, specific surface markers are needed to better characterize these cells and decipher their mechanisms of action. Neuropilin-1 (Nrp-1), a membrane protein primarily involved in the nervous system, was identified as a specific marker of murine Treg, but its expression has not been rigorously investigated in human Treg. Here we show that in contrast to murine Treg and regardless of their origins (blood, thymus, spleen, lymph node or tonsil), human Foxp3 1 Treg do not specifically express Nrp-1. However, a population of Foxp3 À Nrp-1 1 T cells can be detected in human secondary lymphoid organs, and Nrp-1 expression is induced on peripheral blood T lymphocytes upon in vitro activation. We conclude that Nrp-1 cannot be used as a specific marker of human Treg, but might represent a novel activation marker of human T cells both in vitro and in vivo.

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Section: Introductionsupporting

confidence: 77%

Neuropilin‐1 is not a marker of human Foxp3⁺ Treg

et al. 2009

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“…6B). Notably, amounts of SEMA3A released from MV-DC/T-cell co-cultures several fold exceeded those determined to actively inhibit T-cell expansion stimulated allogeneic LPS-DC [34] or on aCD3/CD28 ligation [36]. In line with previous reports [38,39], we repeatedly detected especially in the co-cultures, at least two SEMA3A species (Fig.…”

supporting

confidence: 90%

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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“…[25][26][27] Several distinct mechanisms that contribute to a rapid turnover of CD3-f chain have been proposed that may be responsible for differences observed in CD3-f chain expression in T cells of patients with cancer. [28][29][30] In the present study, it was demonstrated that treatment of HI PBMCs with cell-free supernatants derived from oral tumours led to the down-regulation of CD3-f chain expression in T cells without affecting the other T-cell signalling molecules (ZAP70, CD3-e and p56…”

Section: Discussionmentioning

confidence: 57%

“…26,29,30 The present study reported how extrinsic soluble mediator OAS2 secreted by oral tumour cells modulate CD3-f chain expression in T cells. 38 The 2 0 5 0 -OAS, apart from its antiviral action is involved in other cellular processes such as cell growth and differentiation, gene regulation and apoptosis.…”

Section: Discussionmentioning

confidence: 60%

Extracellular 2′5′‐oligoadenylate synthetase 2 mediates T‐cell receptor CD3‐ζ chain down‐regulation via caspase‐3 activation in oral cancer

et al. 2015

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SummaryDecreased expression of CD3-f chain, an adaptor protein associated with T-cell signalling, is well documented in patients with oral cancer, but the mechanistic justifications are fragmentary. Previous studies in patients with oral cancer have shown that decreased expression of CD3-f chain was associated with decreased responsiveness of T cells. Tumours are known to induce localized as well as systemic immune suppression. This study provides evidence that oral tumour-derived factors promote immune suppression by down-regulating CD3-f chain expression. 2 0 5 0 -Oligoadenylate synthetase 2 (OAS2) was identified by the proteomic approach and our results established a causative link between CD3-f chain down-regulation and OAS2 stimulation. The surrogate situation was established by over-expressing OAS2 in a HEK293 cell line and cell-free supernatant was collected. These supernatants when incubated with T cells resulted in down-regulation of CD3-f chain, which shows that the secreted OAS2 is capable of regulating CD3-f chain expression. Incubation of T cells with cell-free supernatants of oral tumours or recombinant human OAS2 (rh-OAS2) induced caspase-3 activation, which resulted in CD3-f chain down-regulation. Caspase-3 inhibition/down-regulation using pharmacological inhibitor or small interfering RNA restored down-regulated CD3-f chain expression in T cells induced by cell-free tumour supernatant or rh-OAS2. Collectively these results show that OAS2 leads to impairment in CD3-f chain expression, so offering an explanation that might be applicable to the CD3-f chain deficiency observed in cancer and diverse disease conditions.

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Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function

Cited by 145 publications

References 34 publications

Neuropilin‐1 is not a marker of human Foxp3⁺ Treg

Neuropilin‐1 is not a marker of human Foxp3⁺ Treg

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

Extracellular 2′5′‐oligoadenylate synthetase 2 mediates T‐cell receptor CD3‐ζ chain down‐regulation via caspase‐3 activation in oral cancer

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Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function

Cited by 145 publications

References 34 publications

Neuropilin‐1 is not a marker of human Foxp3+ Treg

Neuropilin‐1 is not a marker of human Foxp3+ Treg

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

Extracellular 2′5′‐oligoadenylate synthetase 2 mediates T‐cell receptor CD3‐ζ chain down‐regulation via caspase‐3 activation in oral cancer

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Neuropilin‐1 is not a marker of human Foxp3⁺ Treg

Neuropilin‐1 is not a marker of human Foxp3⁺ Treg