IFN-γ 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-γ 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-γ was only partly MHC class I restricted for pDC, indicating a noncognate CD8+ T cell activation. pDC, but not cDC, matured and secreted IFN-α in the presence of apoptotic H9HIV cells. A mixture of IFN-α, IFN-β, and TNF-α induced intracellular production of IFN-γ but not granzyme B, mimicking the noncognate mechanism. Neutralization of type I IFN signaling blocked noncognate intracellular production of IFN-γ. Moreover, cognate stimulation was required to induce IFN-γ secretion in addition to the cytokine mixture. 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 Ag-specific CD8+ T cell activation against chronic infections or tumors.

Isnard, S., Hatton, E.x., Iannetta, M., Guillerme, J., Hosmalin, A. (2021). Cell-associated {HIV} cross-presentation by plasmacytoid dendritic cells is potentiated by noncognate {CD}8$mathplus$ T cell preactivation. JOURNAL OF IMMUNOLOGY, 207(1), 15-22 [10.4049/jimmunol.2000392].

Cell-associated {HIV} cross-presentation by plasmacytoid dendritic cells is potentiated by noncognate {CD}8$mathplus$ T cell preactivation

Marco Iannetta;
2021-06-01

Abstract

IFN-γ 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-γ 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-γ was only partly MHC class I restricted for pDC, indicating a noncognate CD8+ T cell activation. pDC, but not cDC, matured and secreted IFN-α in the presence of apoptotic H9HIV cells. A mixture of IFN-α, IFN-β, and TNF-α induced intracellular production of IFN-γ but not granzyme B, mimicking the noncognate mechanism. Neutralization of type I IFN signaling blocked noncognate intracellular production of IFN-γ. Moreover, cognate stimulation was required to induce IFN-γ secretion in addition to the cytokine mixture. 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 Ag-specific CD8+ T cell activation against chronic infections or tumors.
giu-2021
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/06 - ONCOLOGIA MEDICA
English
Isnard, S., Hatton, E.x., Iannetta, M., Guillerme, J., Hosmalin, A. (2021). Cell-associated {HIV} cross-presentation by plasmacytoid dendritic cells is potentiated by noncognate {CD}8$mathplus$ T cell preactivation. JOURNAL OF IMMUNOLOGY, 207(1), 15-22 [10.4049/jimmunol.2000392].
Isnard, S; Hatton, Ex; Iannetta, M; Guillerme, J; Hosmalin, A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/276427
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