HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase–dependent mechanism
Olivier Manches, David Munn, Anahita Fallahi, Jeffrey Lifson, Laurence Chaperot, Joel Plumas, Nina Bhardwaj
Olivier Manches, David Munn, Anahita Fallahi, Jeffrey Lifson, Laurence Chaperot, Joel Plumas, Nina Bhardwaj
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Research Article Virology

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

Abstract

Plasmacytoid DCs (pDCs) have been implicated as crucial cells in antiviral immune responses. On recognizing HIV, they become activated, secreting large amounts of IFN-α and inflammatory cytokines, thereby potentiating innate and adaptive antiviral immune responses. Here, we have shown that HIV-stimulated human pDCs can also induce the differentiation of naive CD4+ T cells into Tregs with suppressive function. This differentiation was independent of pDC production of IFN-α and primarily dependent on pDC expression of indoleamine 2,3-dioxygenase, which was induced through the TLR/MyD88 pathway, following binding of HIV to CD4 and triggering of TLR7 by HIV genomic RNA. Functionally, the Tregs induced by pDCs were shown to inhibit the maturation of bystander conventional DCs. This study therefore reveals what we believe to be a novel mechanism by which pDC may regulate and potentially limit anti-HIV immune responses.

Authors

Olivier Manches, David Munn, Anahita Fallahi, Jeffrey Lifson, Laurence Chaperot, Joel Plumas, Nina Bhardwaj

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Figure 5

pDC-induced Tregs inhibit moDC maturation.

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pDC-induced Tregs inhibit moDC maturation. Tregs generated by AT-2 HIV–a...
Tregs generated by AT-2 HIV–activated pDCs were incubated for 24 hours with either pDCs (A) or moDCs (B). The DC subsets were then stimulated with CpGB (A) or resiquimod (B). (A) pDCs were stimulated with increasing doses of CpGB (0, 0.2, 0.4, 2 μg/ml), and their expression of CD40 and CD83 was measured by flow cytometry after 1 day, in the gated CD123hi population (1 representative experiment of 3 is shown). The flow cytometry plot (left panel) shows cells stimulated by 2 μg/ml CpGB. The percentage of cells in the upper-right quadrant (CD40+CD83+) is indicated. (B) moDCs were incubated with different ratios of Tregs/moDCs ([–], 1:1, 3:1), and their expression of CD86 and CD83 was measured by flow cytometry by gating on CD11chi cells. The percentage of cells in the upper-right quadrant (CD86+CD83+) is indicated. *P < 0.01, Student’s t test. Results of 1 representative experiment of 3 are shown.