Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection.

Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Hôpital St.-Luc, Montréal, Québec, Canada.
Nature medicine (Impact Factor: 28.05). 03/2010; 16(4):452-9. DOI: 10.1038/nm.2106
Source: PubMed

ABSTRACT Viral replication and microbial translocation from the gut to the blood during HIV infection lead to hyperimmune activation, which contributes to the decline in CD4+ T cell numbers during HIV infection. Programmed death-1 (PD-1) and interleukin-10 (IL-10) are both upregulated during HIV infection. Blocking interactions between PD-1 and programmed death ligand-1 (PD-L1) and between IL-10 and IL-10 receptor (IL-10R) results in viral clearance and improves T cell function in animal models of chronic viral infections. Here we show that high amounts of microbial products and inflammatory cytokines in the plasma of HIV-infected subjects lead to upregulation of PD-1 expression on monocytes that correlates with high plasma concentrations of IL-10. Triggering of PD-1 expressed on monocytes by PD-L1 expressed on various cell types induced IL-10 production and led to reversible CD4+ T cell dysfunction. We describe a new function for PD-1 whereby microbial products inhibit T cell expansion and function by upregulating PD-1 levels and IL-10 production by monocytes after binding of PD-1 by PD-L1.


Available from: Yoav Peretz, Jun 15, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although monocytes and macrophages are targets of HIV-1-mediated immunopathology, the impact of high viremia on activation-induced monocyte apoptosis relative to monocyte and macrophage activation changes remains undetermined. Here, we determined constitutive and oxidative stress-induced monocyte apoptosis in uninfected and HIV(+) individuals across a spectrum of viral load (n=35, range: 2,243 to 1,355,998 HIV-1 RNA copies/mL) and CD4 count (range: 26 to 801 cells/mm(3)). Both constitutive and oxidative stress-induced apoptosis were positively associated with viral load and negatively associated with CD4 with an elevation in apoptosis occurring in patients with greater than 40,000 (4.6 log) copies/mL. As expected, expression of Rb1 and interferon-stimulated genes (ISGs), plasma sCD163 concentration, and the proportion of CD14+/CD16+ intermediate monocytes were elevated in viremic patients compared to uninfected controls. Although most ISG expression, sCD14, sCD163, and CD14+/CD16+ frequencies were not directly associated with a change in apoptosis, sCD14 and ISG expression showed an association with increasing viral load. Multivariable analysis of clinical values and monocyte gene expression identified changes in IFI27, IFITM2, Rb1, and Bcl2 expression as determinants of constitutive apoptosis (p=3.77×10(-5), adjusted-R(2)=0.5983), while changes in viral load, IFITM2, Rb1, and Bax expression were determinants of oxidative stress-induced apoptosis (p=5.59×10(-5), adjusted-R(2)=0.5996). Our data demonstrate differential activation states in monocytes between levels of viremia in association with differences in apoptosis that may contribute to greater monocyte turnover with high viremia.
    Journal of Virology 10/2014; 89(1). DOI:10.1128/JVI.02382-14 · 4.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Osteoclasts (OCs) are bone resorbing cells whose activity can be regulated by activated T cells and their cytokines. However, the immune function of OCs is largely unknown. In this study, we found that as bystanders, human OCs effectively suppressed T-cell proliferation induced by allogeneic, microbial antigenic and T-cell receptor stimuli in vitro. Mechanistic studies revealed that T cell-derived IFN-γ and CD40 ligand (CD40L) induced the expression of indoleamine 2,3-dioxygenase (IDO) in OCs, which mediated the immunosuppressive function on T-cell proliferation through depleting tryptophan. Neutralizing IFN-γ and blocking CD40L, and silencing or inhibiting IDO in OCs restored T-cell proliferation in the presence of OCs. Our data reveal a novel function of human OCs as inducible immunosuppressive cells, and a feedback loop between OCs and activated T cells. Thus, this study provides new insight into the mechanism of the immunosuppressive function of OCs, and may be helpful for developing novel therapeutic strategies for human diseases involving both the bone and immune systems. © 2014 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 12/2014; 29(12). DOI:10.1002/jbmr.2294 · 6.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Treatment with antiretroviral therapy dramatically increases the survival of HIV-infected individuals. However, treatment has to be continued for life because it does not lead to the full eradication of infection. HIV persists in resting CD4(+) T cells, and possibly other cell types, and can reemerge from these cells when therapy is interrupted. Here, we review molecular mechanisms that have been proposed to contribute to HIV latency, as well as the relative roles of cis- and trans-acting mechanisms. We also discuss existing and future therapeutic opportunities regarding HIV latency that might lead to a future cure for HIV infection.
    Annual Review of Medicine 01/2015; 66(1):407-21. DOI:10.1146/annurev-med-092112-152941 · 15.48 Impact Factor