Cell-Associated HIV Cross-Presentation by Plasmacytoid Dendritic Cells Is Potentiated by Noncognate CD8+ T Cell Preactivation

Abstract

Human plasmacytoid dendritic cells (pDC) can cross-present antigens from apoptotic HIVinfected cells or tumor cells to CD8 + T cells. As pDC respond to HIV virions by maturing and secreting cytokines, we wondered whether these innate properties would affect crosspresentation from HIV-infected cells. We incubated purified blood DC with apoptotic HIVinfected H9 cells and then explored the activation process of HIV-specific cloned CD8 + T cells, in the presence of saquinavir We studied IFN-g secretion by HIV-specific T cells, which is known to be tightly regulated by engagement of the T cell receptor. We found that HIV-specific secretion by cloned HIV-specific CD8 + T cells was stimulated by pDC and cDC1 more than by cDC2, and was strictly MHC-Class I (MHC-I)-restricted. Surprisingly, intracellular production of IFN-γ was only partly MHC-I restricted for pDC, indicating a non-cognate CD8 + T cell activation. Plasmacytoid DC, but not cDC, matured and secreted IFN-a in the presence of apoptotic H9HIV cells. A cocktail of IFN-a, IFN-b and TNF-a induced intracellular production of IFN-γ but not Granzyme-B, mimicked the non-cognate mechanism, and neutralization of type I IFN signaling blocked non-cognate intracellular production of IFN-γ in the co-culture model. Moreover, cognate stimulation was required to induce IFN-γ secretion in addition to the cytokine cocktail. Thus, IFN-γ secretion is tightly regulated by engagement of the TCR as expected, but in the context of virus-infected cells, pDC can trigger intracellular IFN-γ accumulation in CD8 + T cells, potentializing IFN-γ secretion once CD8 + T cells make cognate interactions. These findings may help manipulate type I IFN signaling to enhance specifically antigen-specific CD8 + T cell activation against chronic infections or tumors. • HIV-infected H9 cells induce type I IFN production by pDC • Type I IFN induces IFN-γ but not Granzyme intracellular production in CD8 + T cells • pDC cross-present MHC-I-restricted HIV-Gag antigen to specific CD8 + T cells • IFN-γ secretion is potentiated by type I IFN, but only upon cognate interaction

Toll-like receptor agonists enhance HIV-specific T cell response mediated by plasmacytoid dendritic cells in diverse HIV-1 disease progression phenotypes

“…Classically known for their IFN-α producing abilities, pDCs act also as antigen-presenting cells (APC) 52,53 . pDCs can process and present endogenous and exogenous antigens on MHC I and II molecules and induce antigen-speci c activation of both CD8 and CD4 T-cells [54][55][56][57][58] . It was previously published that the administration of the TLR-9 agonist MGN1703 to PLWH on ART enhances pDCs activation markers and T-cell activation 36 .…”

IgG-Complexed Adenoviruses Induce Human Plasmacytoid Dendritic Cell Activation and Apoptosis

“…When bound by antibodies, viruses are taken up by the Fcγ receptors expressed by numerous cells, including phagocytes [20]. It is likely that FcγR-mediated IC-HAdV5 internalization delivers HAdV components to distinct endosomal compartments for degradation, followed by presentation by MHC II and cross-presentation by MHC I molecules [21]. In contrast to prototype antigens, HAdV5 influences intracellular trafficking.…”