LPS enhances HIV-1-induced maturation and programmed death ligand-1 expression on human plasmacytoid dendritic cells (168.27)

Abstract

Abstract Elevated plasma levels of lipopolysaccharide (LPS) resulting from disruption of gut mucosal integrity during HIV infection has been implicated as a major factor contributing to immune activation that is a hallmark of HIV infection. The negative costimulatory molecule, Programmed Death-1 (PD-1), and its ligand, Programmed Death Ligand -1(PD-L1), negatively regulate the function of exhausted CD8 T cells in chronic HIV-1 infection leading to suppression of specific anti-viral T cell responses. In HIV-infected individuals, increased PD-L1 expression on APCs correlates directly with viral load, indicating a potential effect of the virus on PD-L1 expression. Since the mechanisms of PD-L1 up-regulation in these settings are not understood, we investigated how PD-L1 expression is regulated in plasmacytoid dendritic cells (pDC). We also investigated the influence of LPS on virally stimulated pDC maturation and PD-L1 expression. By kinetic studies, we observed that LPS enhanced HIV-1 induced PD-L1, CD40 and CD83 expression on pDC, and that PD-L1 expression was up-regulated on matured pDC. IFN-α expression preceded PD-L1 expression on pDC following HIV-1 stimulation, but IFN-a by itself only modestly increased PD-L1 expression, indicating that up-regulation of PD-L1 on pDC was specifically a primary response to HIV stimulation. Together, these results suggest that pDC adopt a tolerogenic phenotype following maturation during HIV-1 infection and LPS helps mediate this process.