Role of exosomal BTLA/HVEM signaling in HTLV-1 associated diseases and associated T-cell dysfunction.

Abstract

Abstract Immune checkpoint (ICP) mediators play pivotal roles in regulating a broad spectrum of immune responses against cancer and infectious diseases. In previous studies we have established the role of negative checkpoint receptors (NCRs, PD-1, TIGIT, LAG-3, etc.) in determining the quality of anti-HTLV-1 cytolytic (CTL) response in controlling proviral load and maintaining a asymptomatic state in majority of infected individuals. Interestingly, ICPs can be released in the soluble form and carried on the surface of small extracellular vesicles (50–200 nm) known as exosomes that possess immunomodulatory activity. Consequently, we profiled ICPs in isolated exosomes and culture media of HTLV-1 cell lines representing both HAM/TSP and ATLL. High levels of BTLA (B-and T-Lymphocyte Attenuator) and its ligand HVEM (Herpes virus entry mediator) along with PD-1 (Programmed cell death receptor-1) and its ligand PD-L2 (not PD-L1) were observed in soluble and exosomal forms as well in the sera of HAM patients that carry high proviral load and viral proteins such as Tax. HTLV-1 infection, Tax protein and/or IFNy could serve as causative mechanism for increased ICP levels in HAM patients. Indeed, treatment with anti-retroviral drugs significantly reduced ICP levels confirming specificity of our observations. Functionality of exosomal BTLA/HVEM is being validated in the ongoing studies along with their direct role in regulating CD8 T-cell functions and cytolytic potential upon blockade to provide a novel therapeutic target for HAM/TSP and other neuroinflammatory diseases. Supported by grants from NIH: 1R01NS0971-47, T32-MH079785