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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 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 and Allergy
  • Immunology

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