title: 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.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors: Laboratory of Cellular Physiology and Immunology, Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10065, USA.
authors: Gaëlle
authors: G
authors: Breton
authors: Bader
authors: B
authors: Yassine-Diab
authors: Lillian
authors: L
authors: Cohn
authors: Mohamed-Rachid
authors: MR
authors: Boulassel
authors: Jean-Pierre
authors: JP
authors: Routy
authors: Rafick-Pierre
authors: RP
authors: Sékaly
authors: Ralph M
authors: RM
authors: Steinman
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D016655:HIV Core Protein p24 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D009000:Monocytes / Q000473:pathology / Q000821:virology; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D019151:Peptide Library; D061027:Programmed Cell Death 1 Ligand 2 Protein; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016655:HIV Core Protein p24; D036341:Intercellular Signaling Peptides and Proteins; C556977:PDCD1LG2 protein, human; D010446:Peptide Fragments; D019151:Peptide Library; D061027:Programmed Cell Death 1 Ligand 2 Protein; D034741:RNA, Small Interfering