HERV1-env dependent unfolded protein response activation is a potential initiator of autoreactivity in autoimmune liver disease

Abstract Regulatory T cells are not terminally differentiated but can acquire effector properties. Here we report Human Endogenous Retrovirus 1 (HERV1-env) induction of endoplasmic reticulum (ER) stress with Unfolded Protein Response (UPR) activation, through its interaction with ATF6. UPR activation cleaves ATF6 to its α and β isoforms. ATF6α up-regulates RORC, STAT3 and TBX21 and induces IL-17A and INF-γ production in regulatory T cells by binding to promoter sequences. Silencing of HERV1-env results in partial recovery of regulatory T cell suppressive function and abrogation of apoptosis. These findings identify ER stress and UPR activation as key factors driving regulatory T cell plasticity.