In vivo NKTT320-induced activation of invariant Natural Killer T-cells (iNKTs) and potential applications for use in AIDS pathogenesis modulation

Abstract

Abstract iNKTs are unique, innate T cells with an invariant TCRα chain that recognize glycolipids presented by nonpolymorphic MHC class-I-like CD1d molecules. Activated iNKTs rapidly secrete a range of cytokines and thus have diverse functions including potentiation of anti-tumor and pathogen-specific humoral and cellular immunity and resolution of inflammation. iNKT depletion and dysfunction are common in pathogenic HIV/SIV infection and may hasten AIDS progression. In this study, we tested a novel monoclonal antibody, NKTT320, that specifically binds to the iNKT cell TCRα as a tool for direct in vivo iNKT activation in Mauritian cynomolgus macaques (MCM). Dose-escalation NKTT320 pharmacokinetic studies were performed in 11 SIV-negative MCM. Plasma NKTT320 levels were measured by ELISA while kinetics of iNKT activation and effect on other immune cell subsets were evaluated by flow cytometry. NKTT320 plasma levels peaked between 6.6–47.2 μg/ml within 24 hours of a single IV doses of 100–1000 μg/kg and declined below detection by 4–6 weeks. NKTT320 administration resulted in rapid iNKT activation and proliferation of CD4+ more than CD8+ iNKTs, without non-specific T cell activation. Transient elevation of several plasma analytes (IL-2, IL-6, IL-17, MCP-1, MDC and IP-10) and increased proliferation of non-T immune cell subsets were observed suggesting downstream potentiation of innate and adaptive immunity. Repeated doses of NKTT320 increased iNKT responsiveness indicating that treatment did not lead to iNKT anergy. NKTT320-mediated iNKT activation may be a useful therapeutic tool to preserve and enhance iNKT function, thereby preventing immunodeficiency and aberrant immune activation in pathogenic SIV infection.