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Volume 6 Supplement 3

AIDS Vaccine 2009

P16-52. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism

Background

Plasmacytoid dendritic cells (pDC) are crucial cells implicated in anti-viral immune responses. On recognizing HIV, they become activated, secreting high amounts of IFNα and inflammatory cytokines, thereby potentiating anti-viral innate and adaptive immune responses. However, the role of pDC in adaptive immunity is still debated. Several studies have documented a role for activated pDC in the induction of CD4+ or CD8+ regulatory T cells (Treg), both in vitro and in vivo. A direct correlation between CD8+ T cell activation levels and disease progression levels has been confirmed in many studies. We investigated here whether HIV-stimulated pDC can regulate the levels of immune activation by promoting the differentiation of regulatory CD4+ T cells.

Methods

Freshly purified pDC from normal donors (New York Blood Bank) were incubated for 7 days with purified allogeneic CD4+ CD25- T cells, and their suppressive activity measured in a secondary proliferative assay. CD86/CD83 expression and cytokine secretion by monocyte-derived DC (moDC) induced by LPS or R848 were measured in presence or absence of CD3-activated Treg. siRNA knock-down of NIK and IKKalpha was performed on the leukemic pDC line GEN2.2 and expression of IDO was monitored at the RNA and protein level.

Results

HIV-stimulated pDC were found to induce the differentiation of Treg from naive CD4+ T cells, in an indoleamine 2,3 dioxygenase (IDO)-dependent way. Furthermore, pDC-induced Treg could suppress the Toll-Like Receptor (TLR)-mediated maturation of moDC, partially through CTLA-4 interaction with CD80/CD86. We further show that TLR triggering induces the activation of IDO through the non-canonical NF-κB pathway, as evidenced by knocking-down the expression of NIK and IKKalpha.

Conclusion

This study reveals what we believe to be a novel mechanism by which pDC may regulate and potentially limit anti-HIV immune responses, and identifies a potential target for clinical intervention.

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Correspondence to O Manches.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Manches, O., Munn, D., Fallahi, A. et al. P16-52. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. Retrovirology 6, P281 (2009). https://doi.org/10.1186/1742-4690-6-S3-P281

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Keywords

  • Adaptive Immune Response
  • Adaptive Immunity
  • Suppressive Activity
  • Plasmacytoid Dendritic Cell
  • Crucial Cell