Sensing of cell-associated HTLV by plasmacytoid dendritic cells is regulated by dense β-galactoside glycosylation.

Human T Lymphotropic virus (HTLV) infection can persist in individuals resulting, at least in part, from viral escape of the innate immunity, including inhibition of type I interferon response in infected T-cells. Plasmacytoid dendritic cells (pDCs) are known to bypass viral escape by their robust type I interferon production. Here, we demonstrated that pDCs produce type I interferons upon physical cell contact with HTLV-infected cells, yet pDC activation inversely correlates with the ability of the HTLV-producing cells to transmit infection. We show that pDCs sense surface associated-HTLV present with glycan-rich structure referred to as biofilm-like structure, which thus represents a newly described viral structure triggering the antiviral response by pDCs. Consistently, heparan sulfate proteoglycans and especially the cell surface pattern of terminal -galactoside glycosylation, modulate the transmission of the immunostimulatory RNA to pDCs. Altogether, our results uncover a function of virus-containing cell surface-associated glycosylated structures in the activation of innate immunity. Author summary Human T Lymphotropic virus type (HTLV) establishes persistent infections, leading to adult T-cell Leukemia, a life-threatening cancer in chronically-infected individuals. Viral persistence likely results from a failure of immune responses to eradicate viral replication, a least in part, by viral escape from innate immunity, and notably via decreased production of type I interferons (IFN-I) by infected cells. Plasmacytoid dendritic cells (pDCs) are known as robust producers of IFN-I in response to virus stimulation, thus bypassing the viral mechanisms to evade pathogen-sensing pathways in infected cells. However, HTLV particles are not detected in biological fluids of infected individuals, raising the question of the pDC-activating signal. Here, we demonstrate that pDCs produce IFN-I upon physical contacts with HTLV-infected cells. We show that pDCs sense surface associated-HTLV present with glycan-rich structure, referred to as HTLV-biofilm-like structure. Importantly, the sensing of infected cells by pDCs is modulated by the glycosylation pattern at the surface of infected cells. This newly ascribed regulation of innate immunity activation by cell surface-associated glycans might contribute to the differential activation levels of antiviral response to infected cells when their glycosylation profile is modified, such as for chronically infected cells or tumor cells.