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In vitro HIV infection impairs the capacity of myeloid dendritic cells to induce regulatory T cells.

ABSTRACT: Myeloid dendritic cells (mDCs) are the antigen-presenting cells best capable of promoting peripheral induction of regulatory T cells (Tregs), and are among the first targets of HIV. It is thus important to understand whether HIV alters their capacity to promote Treg conversion. Monocyte-derived DCs (moDCs) from uninfected donors induced a Treg phenotype (CD25(+)FOXP3(+)) in autologous conventional T cells. These converted FOXP3(+) cells suppressed the proliferation of responder T cells similarly to circulating Tregs. In contrast, the capacity of moDCs to induce CD25 or FOXP3 was severely impaired by their in vitro infection with CCR5-utilizing virus. MoDC exposure to inactivated HIV was sufficient to impair FOXP3 induction. This DC defect was not dependent on IL-10, TGF-? or other soluble factors, but was due to preferential killing of Tregs by HIV-exposed/infected moDCs, through a caspase-dependent pathway. Importantly, similar results were obtained with circulating primary myeloid DCs. Upon infection in vitro, these mDCs also killed Treg through mechanisms at least partially caspase-dependent, leading to a significantly lower proportion of induced Tregs. Taken together, our data suggest that Treg induction may be defective when DCs are exposed to high levels of virus, such as during the acute phase of infection or in AIDS patients.

SUBMITTER: Presicce P

PROVIDER: S-EPMC3418294 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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In vitro HIV infection impairs the capacity of myeloid dendritic cells to induce regulatory T cells.

Presicce Pietro P Moreno-Fernandez Maria E ME Rusie Laura K LK Fichtenbaum Carl C Chougnet Claire A CA

PloS one 20120813 8

Myeloid dendritic cells (mDCs) are the antigen-presenting cells best capable of promoting peripheral induction of regulatory T cells (Tregs), and are among the first targets of HIV. It is thus important to understand whether HIV alters their capacity to promote Treg conversion. Monocyte-derived DCs (moDCs) from uninfected donors induced a Treg phenotype (CD25(+)FOXP3(+)) in autologous conventional T cells. These converted FOXP3(+) cells suppressed the proliferation of responder T cells similarly ...[more]

PMID: 22912740

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Project description:Background & aimsHepatitis C virus (HCV) is difficult to eradicate and type III interferons (IFN-?, composed of IL-28A, IL-28B and IL-29) are novel therapeutic candidates. We hypothesized that IFN-? have immunomodulatory effects in HCV- infected individuals.Materials and methodsWe analyzed the expression of IFN-? and its receptor (composed of IL-10R2 and IFN-?R subunits) in the blood and livers of patients with chronic (c)HCV infection compared to controls (those who cleared HCV by sustained virological response, SVR, and those with liver inflammation of non-viral origin, non-alcoholic steatohepatitis, NASH). We also compared the proliferative capacity of dendritic cells (DCs) obtained from healthy individuals and those with chronic HCV using a mixed leukocyte reaction combined with 3H-Td incorporation. In addition, the composition of the IFN-? receptor (IFN-?R) on myeloid DCs, plasmacytoid DCs, PBMCs, and T cells was determined by FACS analysis.ResultsWe report that the expression of IFN-? protein in serum and mRNA in liver is increased in cHCV patients, but not in those with HCV SVR or NASH, compared to controls. Liver level of IFN-?R mirrored the expression of serum IFN-? and was higher in cHCV, compared to controls and HCV-SVR patients, suggesting that elevation of IFN-? and IFN-?R are HCV-dependent. We further identified that innate immune cell populations expressed complete IFN-? receptor. In vitro, recombinant IFN-? promoted differentiation of monocyte-derived dendritic cells (DCs) into a phenotype with low T cell stimulatory capacity and high PD-L1 expression, which further promoted expansion of existing regulatory T cells. IFN-?-DCs failed to induce de novo generation of regulatory T cells. The inhibitory capacity of IFN-?-DCs was counteracted by recombinant IL-12 and by neutralization of the PD-1/PD-L1 system.ConclusionsOur novel findings of the immunomodulatory effect of IFN-? contribute to the understanding of the anti-inflammatory and/or anti-viral potential of IFN-? in cHCV.

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In vitro HIV infection impairs the capacity of myeloid dendritic cells to induce regulatory T cells.

Publications

In vitro HIV infection impairs the capacity of myeloid dendritic cells to induce regulatory T cells.

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