TY - JOUR
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.
N1 - Funding Information:
Acknowledgements We thank Henry A. Zebroski (Proteomics Resource Center, The Rockefeller University) for synthesizing the Ova peptide library. This work was supported by a grant awarded to Argos Therapeutics from the National Institutes of Health (NIAID-DIADS-BAA-06-19). R.-P.S. is the Canada Research Chair in Human Immunology. J.-P.R. is a clinician–scientist supported by Fonds de Recherche en Santé du Québec.
PY - 2009/9
Y1 - 2009/9
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.
KW - CD8 T cell
KW - Dendritic cells
KW - HIV-1 gag
KW - PD-L1
KW - PD-L2
KW - SiRNA
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U2 - 10.1007/s10875-009-9313-9
DO - 10.1007/s10875-009-9313-9
M3 - Article
C2 - 19562472
AN - SCOPUS:69249210916
SN - 0271-9142
VL - 29
SP - 637
EP - 645
JO - Journal of Clinical Immunology
JF - Journal of Clinical Immunology
IS - 5
ER -