Article

In Vitro HIV Infection Impairs the Capacity of Myeloid Dendritic Cells to Induce Regulatory T Cells

Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
PLoS ONE (Impact Factor: 3.23). 08/2012; 7(8):e42802. DOI: 10.1371/journal.pone.0042802
Source: PubMed

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-β 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.

Download full-text

Full-text

Available from: Claire Chougnet, Nov 28, 2014
0 Followers
 · 
107 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of CD4+FOXP3+ regulatory T cells (Treg) in human immunodeficiency virus (HIV) infection has been an area of intensive investigation and remains a matter of ardent debate. Investigation and interpretation suffered from uncertainties concerning Treg quantification. Firstly, Treg quantification and function in HIV infection remain controversial in part because of the lack of reliable and specific markers to identify human Tregs. Secondly, analyzing Treg percentages or absolute numbers led to apparent discrepancies that are now solved: it is now commonly accepted that Treg are targets of HIV infection, but are preferentially preserved compared to conventional CD4 T cells. Moreover, the duality of immune defects associated to HIV infection, i.e., low grade chronic inflammation and defects in HIV-specific responses also casts doubts on the potential impact of Treg on HIV infection. Tregs may be beneficial or/and detrimental to the control of HIV infection by suppressing chronic inflammation or HIV-specific responses respectively. Indeed both effects of Treg suppression have been described in HIV infection. The discovery in recent years of the existence of phenotypically and functionally distinct human CD4+FOXP3+ Treg subsets may provide a unique opportunity to reconcile these contrasting results. It is tempting to speculate that different Treg subsets exert these different suppressive effects. This review summarizes available data concerning Treg fate during HIV infection when considering Treg globally or as subsets. We discuss how the identification of naïve and effector Treg subsets modulates our understanding of Treg biology during HIV infection and the potential impact of HIV infection on mechanisms governing peripheral differentiation of adaptive Tregs.
    Frontiers in Immunology 07/2013; 4:215. DOI:10.3389/fimmu.2013.00215
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Effective prevention of new HIV infections will require understanding the mechanisms involved in HIV acquisition. HIV transmission across the female genital tract is the major mode of new HIV infections in Sub-Saharan Africa and involves complex processes including cell activation, inflammation, and recruitment of HIV target cells. Activated CD4+ T cells, dendritic cells, and macrophages have been described as targets for HIV at the genital mucosa. Activation of these cells may occur in the presence of sexually-transmitted infections, disturbances of commensal flora, and other inflammatory processes. In this review, we discuss causes and consequences of inflammation in the female genital tract, with a focus on dendritic cells. We describe the central role these cells may play in facilitating or preventing HIV transmission across the genital mucosa, and in the initial recognition of HIV and other pathogens, allowing activation of an adaptive immune response to infection. We discuss studies that investigate interventions to limit dendritic cell activation, inflammation and HIV transmission. This knowledge is essential in the development of novel strategies for effective HIV control including microbicides and pre-exposure prophylaxis.
    Innate Immunity 10/2013; DOI:10.1177/1753425913513815 · 3.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tryptophan (Trp) catabolism into immunosuppressive kynurenine (Kyn) by indoleamine 2,3-dioxygenase (IDO) was previously linked to Th17/Treg differentiation and immune activation. Here we examined Trp catabolism and its impact on Th17/Treg balance in uninfected healthy subjects (HS) and a large cohort of HIV-infected patients with different clinical outcomes: ART-naïve, Successfully Treated (ST), and elite controllers (EC). In ART-naïve patients, increased IDO activity/expression, together with elevated levels of TNF-α and sCD40L, were associated with Treg expansion and an altered Th17/Treg balance. These alterations were normalized under ART. In contrast, Trp 2,3-dioxegenase (TDO) expression was dramatically lower in EC when compared to all other groups. Interestingly, EC displayed a distinctive Trp metabolism characterized by low Trp plasma levels similar to ART-naïve patients without accumulating immunosuppressive Kyn levels which was accompanied by a preserved Th17/Treg balance. These results suggest a distinctive Trp catabolism and Th17/Treg balance in HIV progressors and EC. Thus, IDO-induced immune-metabolism may be considered as a new inflammation-related marker for HIV-1 disease progression.
    PLoS ONE 10/2013; 8(10):e78146. DOI:10.1371/journal.pone.0078146 · 3.23 Impact Factor
Show more