Said, E.A. et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4(+) T cell activation during HIV infection. Nat. Med. 16, 452-459

Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Hôpital St.-Luc, Montréal, Québec, Canada.
Nature medicine (Impact Factor: 27.36). 03/2010; 16(4):452-9. DOI: 10.1038/nm.2106
Source: PubMed


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.

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    • "Associated with IBD. Produced by programmed death (PD-1) triggered monocytes (Said et al., 2010). Interleukin-17 (IL-17) Promotes a pro-inflammatory effect and recruitment of neutrophils. "
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    ABSTRACT: Microbial translocation within the context of HIV disease has been described as one of the contributing causes of inflammation and disease progression in HIV infection. HIV-associated symptoms have been related to inflammatory markers and sCD14, a surrogate marker for microbial translocation, suggesting a plausible link between microbial translocation and symptom burden in HIV disease. Similar pathophysiological responses and symptoms have been reported in inflammatory bowel disease (IBD). We provide a comprehensive review of microbial translocation, HIV-associated symptoms, and symptoms connected with inflammation. We identify studies showing a relationship among inflammatory markers, sCD14, and symptoms reported in HIV disease. A conceptual framework and rationale to investigate the link between microbial translocation and symptoms is presented. The impact of inflammation on symptoms supports recommendations to reduce inflammation as part of HIV symptom management. Research in reducing microbial translocation-induced inflammation is limited, but needed, to further promote positive health outcomes among HIV-infected patients.
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    • "The PD-1 molecule delivers an inhibitory signal for T cells [15], [16]. This is illustrated by the immune deficiency of patients with immunodeficiency virus (HIV) infection, in which PD-1 is significantly up-regulated in CD8+ T cells; such pattern of expression is related to impaired function of HIV-specific CD8+ T cells, plasma viral load and IL-10 production [17], [18]. The role of PD-1 in bacterial infections such as Q fever is largely unknown but we reasoned that the chronic evolution of Q fever may be reminiscent of the chronic evolution of HIV infection. "
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    ABSTRACT: Q fever endocarditis, a severe complication of Q fever, is associated with a defective immune response, the mechanisms of which are poorly understood. We hypothesized that Q fever immune deficiency is related to altered distribution and activation of circulating monocyte subsets. Monocyte subsets were analyzed by flow cytometry in peripheral blood mononuclear cells from patients with Q fever endocarditis and controls. The proportion of classical monocytes (CD14+CD16- monocytes) was similar in patients and controls. In contrast, the patients with Q fever endocarditis exhibited a decrease in the non-classical and intermediate subsets of monocytes (CD16+ monocytes). The altered distribution of monocyte subsets in Q fever endocarditis was associated with changes in their activation profile. Indeed, the expression of HLA-DR, a canonical activation molecule, and PD-1, a co-inhibitory molecule, was increased in intermediate monocytes. This profile was not restricted to CD16+ monocytes because CD4+ T cells also overexpressed PD-1. The mechanism leading to the overexpression of PD-1 did not require the LPS from C. burnetii but involved interleukin-10, an immunosuppressive cytokine. Indeed, the incubation of control monocytes with interleukin-10 led to a higher expression of PD-1 and neutralizing interleukin-10 prevented C. burnetii-stimulated PD-1 expression. Taken together, these results show that the immune suppression of Q fever endocarditis involves a cross-talk between monocytes and CD4+ T cells expressing PD-1. The expression of PD-1 may be useful to assess chronic immune alterations in Q fever endocarditis.
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    • "Second, PD-1 signaling may function in APCs independently of TCR or BCR activation. One example is that the ligation of monocyte PD-1 with PD-L1 directly stimulates IL-10 production, leading to reversible CD4 + T-cell dysfunction after HIV infection (Said et al., 2010). In addition, cross-linking of PD-L2 on DCs with specific IgM directly stimulates DC functions and activates groups of genes involved in cell migration and survival (Blocki et al., 2006). "
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    ABSTRACT: Immune responses in the central nervous system (CNS), which involve both resident glial cells and infiltrating peripheral immune cells, play critical roles in the progress of brain injuries and neurodegeneration. To avoid inflammatory damage to the compromised brain, the immune cell activities in the CNS are controlled by a plethora of chemical mediators and signal transduction cascades, such as inhibitory signaling through programed death-1 (PD-1) and programed death ligand (PD-L) interactions. An increasing number of recent studies have highlighted the importance of PD-1/PD-L pathway in immune regulation in CNS disorders such as ischemic stroke, multiple sclerosis, and Alzheimer's disease. Here, we review the current knowledge of the impact of PD-1/PD-L signaling on brain injury and neurodegeneration. An improved understanding of the function of PD-1/PD-L in the cross-talk between peripheral immune cells, CNS glial cells, and non-immune CNS cells is expected to shed further light on immunomodulation and help develop effective and safe immunotherapies for CNS disorders.
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