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HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase–dependent mechanism
Olivier Manches, … , Joel Plumas, Nina Bhardwaj
Olivier Manches, … , Joel Plumas, Nina Bhardwaj
Published September 5, 2008
Citation Information: J Clin Invest. 2008;118(10):3431-3439. https://doi.org/10.1172/JCI34823.
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Research Article Virology

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

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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 1

HIV-activated pDCs induce Tregs from naive CD4+ T cells.

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HIV-activated pDCs induce Tregs from naive CD4+ T cells.
   
(A) AT-2 HI...
(A) AT-2 HIV– or CpGB- or resiquimod-activated pDCs (donor A) were incubated with naive CD4+ T cells (donor B) for 7 days. The responding T cells were then added to a primary allogeneic MLR (the composition of which is displayed in the inset) using PBMCs (A APC) as stimulatory cells and naive CD4+ T cells (B Tn) as responding cells. “CD4” refers to the naive T cells alone; “CD4 + APC” refers to the MLR of the naive CD4+ T cells to PBMCs. Proliferation was measured by thymidine incorporation after 5 days. *P < 0.01, Student’s t test, compared with proliferation of naive T cells in the MLR (far-left black bar). Results shown are representative of 5 experiments. (B) pDCs were activated by AT-2 HIV and incubated with naive CD4+ T cells. The T cells (T/pDC-HIV) were then added at different ratios to naive CD4+ T cells stimulated with anti-CD3 and anti-CD28 antibodies, and proliferation (thymidine incorporation) was measured after 5 days. *P < 0.01, Student’s t test, compared with proliferation of naive T cells alone. Results are representative of 3 experiments. (C) Phenotype of the day 7 T cell population generated by HIV-activated or unactivated pDCs, gated on CD4+ T cells. Expression of CD127 and Foxp3 is shown. Percentages of cells in each gate (Foxp3+CD127lo) are indicated. (D) T cells generated as in B were separated into CD25– and CD25+ populations by magnetic bead enrichment and then added to naive T cells (Tn) and stimulated as described in B. Proliferation was measured after 5 days. Results are representative of more than 5 experiments. (E) T cells stimulated as in B were added to naive CD4+ T cells in the upper chamber of a Transwell plate or in the same lower compartment as naive CD4+ T cells stimulated with anti-CD3 and anti-CD28 antibodies. Proliferation was measured after 5 days by thymidine incorporation. Results are representative of 3 experiments. *P < 0.01, Student’s t test, compared with proliferation of naive T cells alone.

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