Inhibition of NF-κB during human dendritic cell differentiation generates anergy and regulatory T-cell activity for one but not two human leukocyte antigen DR mismatches

Ana Hernandez, Melissa Burger, Bonnie B. Blomberg, William A. Ross, Jeffrey J. Gaynor, Inna Lindner, Robert Cirocco, James M. Mathew, Manuel Carreno, Yidi Jin, Kelvin P. Lee, Violet Esquenazi, Joshua Miller

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

We examined the in vitro inhibition of human monocyte-derived dendritic cells (DC) maturation via NF-κB blockade on T-cell allostimulation, cytokine production, and regulatory T-cell generation. DC were generated from CD14+ monocytes isolated from peripheral blood using GM-CSF and IL-4 for differentiation and TNF-α, IL-1β, and PGE2 as maturational stimuli with or without the NF-κB inhibitors, BAY 11-7082 (BAY-DC) or Aspirin (ASA-DC). Stimulator and responder cells were one versus two HLA-DR mismatched in direct versus indirect presentation assays. Both BAY-DC and ASA-DC expressed high levels of HLA-DR and CD86 but always expressed less CD40 compared with controls. Some experiments showed slightly lower levels of CD80. Both BAY- and ASA- allogeneic DC and autologous alloantigen pulsed DC were weaker stimulators of T cells (by MLR) compared with controls, and there was reduced IL-2 and IFN-γ production by T cells stimulated with BAY-DC or ASA-DC (by ELISPOT) (more marked results were always observed with ASA-treated DC). In addition, NF-κB blockade of DC maturation caused the generation of T cells with regulatory function (T regs) but only when T cells were stimulated by either allogeneic (direct presentation) or alloantigen pulsed autologous DC (indirect presentation) with one HLA-DR mismatch and not with two HLA-DR mismatches (either direct or indirect presentation). However, the T regs generated from these ASA-DC showed similar FoxP3 mRNA expression to those from nontreated DC. Extension of this study to human organ transplantation suggests potential therapies using one DR-matched NF-κB blocked DC to help generate clinical tolerance.

Original languageEnglish (US)
Pages (from-to)715-729
Number of pages15
JournalHuman Immunology
Volume68
Issue number9
DOIs
StatePublished - Sep 2007

Keywords

  • Allorecognition
  • Dendritic cells
  • FoxP3
  • NF-κB inhibitors
  • T reg

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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