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

IFN-gamma secretion by Ag-specific T cells is known to be tightly regulated by engagement of the TCR. Human plasmacytoid dendritic cells (pDC) can cross-present Ags from apoptotic HIV-infected cells or tumor cells to CD8(+) T cells. As pDC respond to HIV virions by maturing and secreting cytokines, we hypothesized that this might affect cross-presentation from HIV-infected cells. Purified blood DC were incubated with apoptotic HIV-infected H9 cells in the presence of saquinavir, after which the activation process of HIV-specific cloned CD8(+) T cells was studied. IFN-gamma secretion by HIV-specific T cells was stimulated by pDC and conventional DC (cDC1) more than by cDC2 and was strictly MHC class I restricted. Surprisingly, intracellular production of IFN-gamma was only partly MHC class I restricted for pDC, indicating a noncognate CD8(+) T cell activation. pDC, but not cDC, matured and secreted IFN-alpha in the presence of apoptotic H9HIV cells. A mixture of IFN-alpha, IFN-beta, and TNF-alpha induced intracellular production of IFN-gamma but not granzyme B, mimicking the noncognate mechanism. Neutralization of type I IFN signaling blocked noncognate intracellular production of IFN-gamma. Moreover, cognate stimulation was required to induce IFN-gamma secretion in addition to the cytokine mixture. Thus, IFN-gamma secretion is tightly regulated by engagement of the TCR as expected, but in the context of virus-infected cells, pDC can trigger intracellular IFN-gamma accumulation in CD8(+) T cells, potentializing IFN-gamma secretion once CD8(+) T cells make cognate interactions. These findings may help manipulate type I IFN signaling to enhance specifically Ag-specific CD8(+) T cell activation against chronic infections or tumors.