P16-52. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism
Retrovirology volume 6, Article number: P281 (2009)
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.
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.
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.
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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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 (Suppl 3), P281 (2009). https://doi.org/10.1186/1742-4690-6-S3-P281