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

Abstract

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...

SEMA6A is a prognostic biomarker in glioblastoma

“…Mock, control, low SEMA6A concentration, and high SEMA6A concentration groups were set up by applied same volume (200 μl) DMEM, solvent (distilled water), and recombinant human SEMA6A (Cat# 11189-H08H, final concentration: 150 ng/ml, 250 ng/ml, Sino Biological Inc, Beijing, China) in medium, respectively [21]. When cultured for 1, 2, 3, 4, 5, 6 days, respectively, cell proliferation was analyzed by MTT assay.…”

Diverse roles for semaphorin−plexin signaling in the immune system

“…In viral infection, Sema3A is also involved in virus-induced immune suppression. Measles virus (MV)-infected DCs, which fail to promote T cell expansion, have greater early Sema3A secretion, resulting in a loss of actin-based protrusion on T cells [71]. Sema3A also has therapeutic potential in pathological immune disorders.…”

The Role of Sphingomyelin Breakdown in Measles Virus Immunmodulation

“…There is, however, evidence that the majority of conjugates formed between T cells and infected DCs is unstable and does not sustain Ca 2+- mobilization in T cells [22]. It appears that in addition to inadequate expression and recruitment of repulsion receptors and their ligands inhibitory signals provided by the viral glycoprotein on the DC surface to conjugating T cells are essentially involved in this process [23,24], thereby rendering MV uptake for subsequent replication highly important in DC-mediated T cell silencing.…”