HMGB1 Is Involved in IFN-α Production and TRAIL Expression by HIV-1-Exposed Plasmacytoid Dendritic Cells: Impact of the Crosstalk with NK Cells

Abstract

Plasmacytoid dendritic cells (pDCs) are innate sensors of viral infections and important mediators of antiviral innate immunity through their ability to produce large amounts of IFN-α. Moreover, Toll-like receptor 7 (TLR7) and 9 (TLR9) ligands, such as HIV and CpG respectively, turn pDCs into TRAIL-expressing killer pDCs able to lyse HIV-infected CD4+ T cells. NK cells can regulate antiviral immunity by modulating pDC functions, and pDC production of IFN-α as well as cell–cell contact is required to promote NK cell functions. Impaired pDC-NK cell crosstalk was reported in the setting of HIV-1 infection, but the impact of HIV-1 on TRAIL expression and innate antiviral immunity during this crosstalk is unknown. Here, we report that low concentrations of CCR5-tropic HIV-1Ba-L promote the release of pro-inflammatory cytokines such as IFN-α, TNF-α, IFN-γ and IL-12, and CCR5-interacting chemokines (MIP-1α and MIP-1β) in NK-pDCs co-cultures. At high HIV-1BaL concentrations, the addition of NK cells did not promote the release of these mediators, suggesting that once efficiently triggered by the virus, pDCs could not integrate new activating signals delivered by NK cells. However, high HIV-1BaL concentrations were required to trigger IFN-α-mediated TRAIL expression at the surface of both pDCs and NK cells during their crosstalk. Interestingly, we identified the alarmin HMGB1, released at pDC-NK cell synapse, as an essential trigger for the secretion of IFN-α and IFN-related soluble mediators during the interplay of HIV-1 exposed pDCs with NK cells. Moreover, HMGB1 was found crucial for mTRAIL translocation to the plasma membrane of both pDCs and NK cells during their crosstalk following pDC exposure to HIV-1. Data from serum analyses of circulating HMGB1, HMGB1-specific antibodies, sTRAIL and IP-10 in a cohort of 67 HIV-1+ patients argue for the in vivo relevance of these observations. Altogether, these findings identify HMGB1 as a trigger for IFN-α-mediated TRAIL expression at the surface of pDCs and NK cells, and they suggest a novel mechanism of innate control of HIV-1 infection.

The Significance of Type-I Interferons in the Pathogenesis and Therapy of Human Immunodeficiency Virus 1 Infection

“…Cell free virus are taken up by pDCs through endocytosis mediated by envelope–CD4 interaction ( 23 , 24 ), while cell-associated virus enter pDCs by fusion or endocytosis ( 14 ). Although cell-associated viruses are at a high level in vivo , they are a less potent inducer of IFN-I than cell free virus ( 25 ). One of the possible reasons is that most of cell-associated viruses are defective viruses which are not able to induce effective immune responses.…”

Dendritic Cell Immune Responses in HIV-1 Controllers

“…From a functional perspective, levels of IFN- secretion in pDC from controllers and HIV-1-negative individuals are not noticeably different, but clearly exceed those of HIV progressors, which downregulate the CD4 receptor and may become refractory to antigenic stimulation due to elevated plasma levels of IFN- and other pro-inflammatory cytokines [53, 54]. In line with these observations, three-dimensional microscopic imaging indicated that pDCs from controllers and healthy donors, but not from progressors, contained high levels of intracellular TRAIL that is recycled to the membrane after HIV exposure and can induce apoptosis in virally infected CD4 T cells in a process that was recently described to be regulated by the alarmin HMGB1 [53, 55]. In contrast, pDCs from viremic patients appeared to constitutively express TRAIL on the cell surface without any viral stimulation, which may contribute to unspecific induction of cell death in CD4 T cells and may by this mechanism aggravate CD4 T cell losses and cellular immune deficiency.…”

Expression of TIM-3 on Plasmacytoid Dendritic Cells as a Predictive Biomarker of Decline in HIV-1 RNA Level during ART

“…Our results show that over a period of 9-months, ART partially restored pDC numbers, however, the immunogenic phenotype of pDCs was not significantly restored. While impairment of single pDC functions was demonstrated in several reports [ 15 , 18 , 19 , 30 , 31 ], in the present study we analyzed a complex dysfunction of pDC covering expression of the MHC class II ligand, the high affinity HIV-1 receptor CD4, the regulatory receptor BDCA-2, the Fcγ receptor CD32, the pDC dysfunction marker TIM-3, and the marker of killer pDC, TRAIL.…”