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

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 env‐binding 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 Ca²⁺ 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.