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 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.
Institute for Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany.
Jonas
J
Hummel
Department of Obstetrics and Gynaecology, University of Wuerzburg, Wuerzburg, Germany.
Ulrike
U
Kämmerer
Institute for Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany.
Nora
N
Müller
Institute for Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany.
Elita
E
Avota
Institute for Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany.
Sibylle
S
Schneider-Schaulies
D026962:Amino Acid Transport System ASC / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation; D002460:Cell Line; D002822:Choriocarcinoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003412:Cricetulus; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D020077:Endogenous Retroviruses / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D010641:Phenotype; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*
D026962:Amino Acid Transport System ASC; D016207:Cytokines; D015686:Gene Products, env; D011257:Pregnancy Proteins; D014759:Viral Envelope Proteins; C405335:syncytin
DC/T-cell conjugates; DCs; HERV; Immune tolerance; Immunological synapse; T-cell activation