SiRNA knockdown of PD-L1 and PD-L2 in monocyte-derived dendritic cells only modestly improves proliferative responses to gag by CD8+ T cells from HIV-1-infected individuals

Gaëlle Breton, Bader Yassine-Diab, Lillian Cohn, Mohamed Rachid Boulassel, Jean Pierre Routy, Rafick Pierre Sékaly, Ralph M. Steinman

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Introduction: Due to their capacity to elicit and regulate immunity, dendritic cells (DCs) are important targets to improve vaccination. Knowing that programmed death-1 (PD-1) high virus-specific T cells become functionally exhausted during chronic exposure to human immunodeficiency virus-1 (HIV-1), the development of a therapeutic DC-based HIV-1 vaccine might include strategies that downregulate PD-L1 and PD-L2 counter-receptors. Methods: After showing that monocyte-derived DCs rapidly upregulated PD-L1 and PD-L2 expression upon maturation with a variety of stimuli, e.g., Toll-like receptor ligands and cytokines, we determined that PD-L1 and PD-L2 expression could be knocked down by electroporation of a single small interfering RNA (siRNA) sequence twice at the monocyte and immature stages of DC development. This knockdown approached completion and was specific and lasting for several days. Results: We then added the PD-L1 and PD-L2 silenced monocyte-derived DCs to peripheral blood mononuclear cells from HIV-1-infected individuals along with pools of 15-mer HIV-1 Gag p24 peptides. However, in cultures from six patients, there was only a modest enhancing effect of PD-L1 and PD-L2 silencing on CD8+ T cell proliferative responses to the DCs. Discussion: These findings suggest that, in monocyte-derived DCs, additional strategies than PD-L1 or PD-L2 blockade will be needed to improve the function of PD-1 high T cells.

Original languageEnglish
Pages (from-to)637-645
Number of pages9
JournalJournal of Clinical Immunology
Volume29
Issue number5
DOIs
Publication statusPublished - Sep 2009

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Dendritic Cells
HIV-1
Monocytes
T-Lymphocytes
Electroporation
Toll-Like Receptors
Small Interfering RNA
Immunity
Blood Cells
Vaccination
Down-Regulation
Vaccines
Cytokines
Ligands
Viruses
Peptides

Keywords

  • CD8 T cell
  • Dendritic cells
  • HIV-1 gag
  • PD-L1
  • PD-L2
  • SiRNA

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

SiRNA knockdown of PD-L1 and PD-L2 in monocyte-derived dendritic cells only modestly improves proliferative responses to gag by CD8+ T cells from HIV-1-infected individuals. / Breton, Gaëlle; Yassine-Diab, Bader; Cohn, Lillian; Boulassel, Mohamed Rachid; Routy, Jean Pierre; Sékaly, Rafick Pierre; Steinman, Ralph M.

In: Journal of Clinical Immunology, Vol. 29, No. 5, 09.2009, p. 637-645.

Research output: Contribution to journalArticle

Breton, Gaëlle ; Yassine-Diab, Bader ; Cohn, Lillian ; Boulassel, Mohamed Rachid ; Routy, Jean Pierre ; Sékaly, Rafick Pierre ; Steinman, Ralph M. / SiRNA knockdown of PD-L1 and PD-L2 in monocyte-derived dendritic cells only modestly improves proliferative responses to gag by CD8+ T cells from HIV-1-infected individuals. In: Journal of Clinical Immunology. 2009 ; Vol. 29, No. 5. pp. 637-645.
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T1 - SiRNA knockdown of PD-L1 and PD-L2 in monocyte-derived dendritic cells only modestly improves proliferative responses to gag by CD8+ T cells from HIV-1-infected individuals

AU - Breton, Gaëlle

AU - Yassine-Diab, Bader

AU - Cohn, Lillian

AU - Boulassel, Mohamed Rachid

AU - Routy, Jean Pierre

AU - Sékaly, Rafick Pierre

AU - Steinman, Ralph M.

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N2 - Introduction: Due to their capacity to elicit and regulate immunity, dendritic cells (DCs) are important targets to improve vaccination. Knowing that programmed death-1 (PD-1) high virus-specific T cells become functionally exhausted during chronic exposure to human immunodeficiency virus-1 (HIV-1), the development of a therapeutic DC-based HIV-1 vaccine might include strategies that downregulate PD-L1 and PD-L2 counter-receptors. Methods: After showing that monocyte-derived DCs rapidly upregulated PD-L1 and PD-L2 expression upon maturation with a variety of stimuli, e.g., Toll-like receptor ligands and cytokines, we determined that PD-L1 and PD-L2 expression could be knocked down by electroporation of a single small interfering RNA (siRNA) sequence twice at the monocyte and immature stages of DC development. This knockdown approached completion and was specific and lasting for several days. Results: We then added the PD-L1 and PD-L2 silenced monocyte-derived DCs to peripheral blood mononuclear cells from HIV-1-infected individuals along with pools of 15-mer HIV-1 Gag p24 peptides. However, in cultures from six patients, there was only a modest enhancing effect of PD-L1 and PD-L2 silencing on CD8+ T cell proliferative responses to the DCs. Discussion: These findings suggest that, in monocyte-derived DCs, additional strategies than PD-L1 or PD-L2 blockade will be needed to improve the function of PD-1 high T cells.

AB - Introduction: Due to their capacity to elicit and regulate immunity, dendritic cells (DCs) are important targets to improve vaccination. Knowing that programmed death-1 (PD-1) high virus-specific T cells become functionally exhausted during chronic exposure to human immunodeficiency virus-1 (HIV-1), the development of a therapeutic DC-based HIV-1 vaccine might include strategies that downregulate PD-L1 and PD-L2 counter-receptors. Methods: After showing that monocyte-derived DCs rapidly upregulated PD-L1 and PD-L2 expression upon maturation with a variety of stimuli, e.g., Toll-like receptor ligands and cytokines, we determined that PD-L1 and PD-L2 expression could be knocked down by electroporation of a single small interfering RNA (siRNA) sequence twice at the monocyte and immature stages of DC development. This knockdown approached completion and was specific and lasting for several days. Results: We then added the PD-L1 and PD-L2 silenced monocyte-derived DCs to peripheral blood mononuclear cells from HIV-1-infected individuals along with pools of 15-mer HIV-1 Gag p24 peptides. However, in cultures from six patients, there was only a modest enhancing effect of PD-L1 and PD-L2 silencing on CD8+ T cell proliferative responses to the DCs. Discussion: These findings suggest that, in monocyte-derived DCs, additional strategies than PD-L1 or PD-L2 blockade will be needed to improve the function of PD-1 high T cells.

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