Human endogenous retrovirus envelope proteins target dendritic cells to suppress T‐cell activation

Abstract

Though mostly defective, human endogenous retroviruses (HERV)can retain open reading frames, which are especially expressed in the placenta. There, the envelope (env) proteins of HERV-W (Syncytin-1), HERV-FRD (Syncytin-2), and HERV-K (HML-2) were implicated in tolerance against the semi-allogenic fetus. Here, we show that the known HERV envbinding receptors ASCT-1 and -2 and MFSD2 are expressed by DCs and T-cells. When used as effectors in coculture systems, CHO cells transfected to express Syncytin-1, -2, or HML-2 did not affect T-cell expansion or overall LPS-driven phenotypic DC maturation, however, promoted release of IL-12 and TNF-α rather than IL-10. In contrast, HERV env expressing choriocarcinoma cell lines suppressed T-cell proliferation and LPS-induced TNF-α and IL-12 release, however, promoted IL-10 accumulation, indicating that these effects might not rely on HERV env interactions. However, DCs conditioned by choriocarcinoma, but also transgenic CHO cells failed to promote allogenic T-cell expansion. This was associated with a loss of DC/T-cell conjugate frequencies, impaired Ca 2+ mobilization, and aberrant patterning of f-actin and tyrosine phosphorylated proteins in T-cells. Altogether, these findings suggest that HERV env proteins target T-cell activation indirectly by modulating the stimulatory activity of DCs.Keywords: DCs r DC/T-cell conjugates r HERV r Immune tolerance r Immunological synapse r T-cell activation Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHuman endogenous retroviruses (HERVs) are estimated to comprise about 8% of the human genome [1]. They are mainly germline transmitted. HERVs are typically defective as a result of multiple mutations in their genomes, and it is therefore only on exception that viral particles can be produced [1,2]. Endogenous retroviruses (ERVs) can substantially regulate host cell gene expression and functions. In addition to viral transcripts, ERV encoded proteins translated from intact ORFs were implicated Correspondence: Dr. Sibylle Schneider-Schaulies e-mail: s-s-s@vim.uni-wuerzburg.de in both pathological and physiological processes [3]. The latter has for instance been revealed for the envelope (env) regions of three HERVs (ERV-3, HERV-W, and HERV-FRD). These are highly expressed in early and late placentae, and their importance in successful accomplishment of pregnancy has been suggested [4][5][6][7][8][9][10], not least because spontaneous abortions or complications of gestation like preeclampsia are associated with reduced levels of HERV env proteins [11,12]. In fact, their expression has been found crucial in the intrauterine fetal development in promoting syncytiotrophoblast formation, while the HERV-FRD env was also associated with fetomaternal tolerance to prevent rejection of the fetus [13][14][15][16][17].Immunodeficiency is commonly associated with retroviral infections (for a recent review see [18] effector mechanisms studied, immunosuppressive domains (ISD) we...

Syncytins enable novel possibilities to transduce human or mouse primary B cells and to achieve well-toleratedin vivogene transfer

“…ASCT2 and MFSD2a which are respectively the entry receptors for syncytin-1 and syncytin-2 (15,17) were readily detected on CD19+ human blood B cells using indirect immunofluorescence and flow cytometry ( Figure 5A). These receptors were also detected on CD11c+ dendritic/myeloid cells and at lower levels on CD3+ T cells as previously reported by others (37). Approximately 50% of blood CD19+ cells and of CD11c+ cells expressed detectable levels of ASCT2 and of MSFD2A whereas only about 10% of CD3+ T cells were positive ( Figure 5B).…”

“…The mechanism of action of this peptide sequence remains unclear. It has been postulated to involve antigenpresenting cells by modulating dendritic cell-mediated T cell activation (37) or could directed reduce the activation of T cells as shown by peptide-treated T cell lines (38). Our results suggest that B cells could potentially be involved and further studies are warranted on this aspect.…”

Syncytin‐1/HERV‐W envelope is an early activation marker of leukocytes and is upregulated in multiple sclerosis patients

“…These data support the role of this protein in the first steps of immune cell activation. In a previous study, syncytin‐1 transfected cells were found to release pro‐inflammatory cytokines IL‐12p70 and TNF‐α [29]. In another work that studied the immunological role of placental syncytin, the authors found that both recombinant syncytin‐1 and syncytin 1‐positive trophoblast microvesicles, induced PBMC activation, indicated by the production of cytokines and chemokines [30].…”

HIV Envelope gp120 Alters T Cell Receptor Mobilization in the Immunological Synapse of Uninfected CD4 T Cells and Augments T Cell Activation

“…For example, the presence of HERV Env on dendritic cells reduces the ability of dendritic cells to form immunological synapses with T cells, resulting in blockage of T cell activation (58). Similarly, the Nef proteins of most SIV and HIV-2 strains have been shown to downregulate TCR and CD3 expression in virus-infected T cells, resulting in the suppression of immunological synapse formation with APCs (48).…”