Sharpe, A.H., Wherry, E.J., Ahmed, R. & Freeman, G.J. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat. Immunol. 8, 239-245

Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Nature Immunology (Impact Factor: 20). 04/2007; 8(3):239-45. DOI: 10.1038/ni1443
Source: PubMed


The programmed cell death 1 (PD-1) surface receptor binds to two ligands, PD-L1 and PD-L2. Studies have shown that PD-1-PD-L interactions control the induction and maintenance of peripheral T cell tolerance and indicate a previously unknown function for PD-L1 on nonhematopoietic cells in protecting tissues from autoimmune attack. PD-1 and its ligands have also been exploited by a variety of microorganisms to attenuate antimicrobial immunity and facilitate chronic infection. Here we examine the functions of PD-1 and its ligands in regulating antimicrobial and self-reactive T cell responses and discuss the therapeutic potential of manipulating this pathway.

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    • "SCV form strain 22 WT (confirmed by rep-PCR) 61 WT S. epidermidis wild-type isolate form septic implant loosening 61 SCV S. epidermidis haemin auxotroph SCV form strain 61 WT (confirmed by rep-PCR) production, in particular the production of IL-10, which is known to down-regulate immunopathology and host defense mechanisms (Rodriguez-Garcia et al., 2011; Thi et al., 2012). Although many regulatory pathways may contribute to the persistence of intracellular bacteria, it will be useful to determine the function of the PD-L1/PD-L2 pathway in such settings (Sharpie et al., 2007). "
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    ABSTRACT: Staphylococcus epidermidis is commonly involved in biomaterial-associated infections. Bacterial small colony variants (SCV) seem to be well adapted to persist intracellularly in professional phagocytes evading the host immune response. We studied the expression of PD-L1/L2 on macrophages infected with clinical isolates of S. epidermidis SCV and their parent wild type (WT) strains. The cytokine pattern which is triggered by the examined strains was also analysed. In the study, we infected macrophages with S. epidermidis WT and SCV strains. Persistence and release from macrophages were monitored via lysostaphin protection assays. Moreover, the effect of IFN-γ pre-treatment on bacterial internalisation was investigated. Expression of PD-L1/L2 molecules was analysed with the use of FACS. Inflammatory reaction was measured by IL-10, TNF-α ELISAs, and transcriptional induction of TNF-α. Our study revealed that clinical SCV isolates were able to persist and survive in macrophages for at least 3 days with a low cytotoxic effect and a reduced proinflammatory response as compared to WT strains. Bacteria upregulated PD-L1/L2 expression on macrophages as compared to non-stimulated cells. The results demonstrated that the ability of S. epidermidis SCVs to induce elevated levels of anti-inflammatory cytokine, IL-10, and reduced transcriptional induction of TNF-α, together with expression of PD-L1 on macrophages and the ability to persist intracellularly without damaging the host cell could be the key factor contributing to chronicity of SCV infections.
    Full-text · Article · Aug 2015 · The Journal of Microbiology
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    • "Negative immune regulators such as Programmed Death-1 (PD-1) and Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) are part of a large network of immune checkpoints that are tightly regulated in order to limit exaggerated immune responses and prevent autoimmunity [1-4]. However, in some instances such as persistent antigenic stimulation during chronic HIV or other viral infections, these negative regulators accumulate progressively on the cell surface of total and Ag-specific T and B cells [5-9]. "
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    ABSTRACT: Background Coexpression of CD160 and PD-1 on HIV-specific CD8+ T-cells defines a highly exhausted T-cell subset. CD160 binds to Herpes Virus Entry Mediator (HVEM) and blocking this interaction with HVEM antibodies reverses T-cell exhaustion. As HVEM binds both inhibitory and activatory receptors, our aim in the current study was to assess the impact of CD160-specific antibodies on the enhancement of T-cell activation.Methods Expression of the two CD160 isoforms; glycosylphosphatidylinositol-anchored (CD160-GPI) and the transmembrane isoforms (CD160-TM) was assessed in CD4 and CD8 primary T-cells by quantitative RT-PCR and Flow-cytometry. Binding of these isoforms to HVEM ligand and the differential capacities of CD160 and HVEM specific antibodies to inhibit this binding were further evaluated using a Time-Resolved Fluorescence assay (TRF). The impact of both CD160 and HVEM specific antibodies on enhancing T-cell functionality upon antigenic stimulation was performed in comparative ex vivo studies using primary cells from HIV-infected subjects stimulated with HIV antigens in the presence or absence of blocking antibodies to the key inhibitory receptor PD-1.ResultsWe first show that both CD160 isoforms, CD160-GPI and CD160-TM, were expressed in human primary CD4+ and CD8+ T-cells. The two isoforms were also recognized by the HVEM ligand, although this binding was less pronounced with the CD160-TM isoform. Mechanistic studies revealed that although HVEM specific antibodies blocked its binding to CD160-GPI, surprisingly, these antibodies enhanced HVEM binding to CD160-TM, suggesting that potential antibody-mediated HVEM multimerization and/or induced conformational changes may be required for optimal CD160-TM binding. Triggering of CD160-GPI over-expressed on Jurkat cells with either bead-bound HVEM-Fc or anti-CD160 monoclonal antibodies enhanced cell activation, consistent with a positive co-stimulatory role for CD160-GPI. However, CD160-TM did not respond to this stimulation, likely due to the lack of optimal HVEM binding. Finally, ex vivo assays using PBMCs from HIV viremic subjects showed that the use of CD160-GPI-specific antibodies combined with blockade of PD-1 synergistically enhanced the proliferation of HIV-1 specific CD8+ T-cells upon antigenic stimulation.Conclusions Antibodies targeting CD160-GPI complement the blockade of PD-1 to enhance HIV-specific T-cell responses and warrant further investigation in the development of novel immunotherapeutic approaches.
    Full-text · Article · Sep 2014 · Journal of Translational Medicine
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    • "Indeed helminths have been shown to induce immune suppression, primarily due to the ability of helminth antigens to drive the immune bias toward a Th2 type response [12], [18], [64]. Th2 responses activate or expand AAMs, which express various negative signaling accessory molecules that induce T cell anergy and downregulate the proliferation of activated T cells [18], [65], [66]. However, the cytokines produced in the CNS during M. corti infection are indicative of a mixed T helper response but with IL-4, IL-13 and IL-10 detected in relatively low amounts [27]. "
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    ABSTRACT: Helminth parasites cause persistent infections in humans and yet many infected individuals are asymptomatic. Neurocysticercosis (NCC), a disease of the central nervous system (CNS) caused by the cestode Taenia solium, has a long asymptomatic phase correlated with an absence of brain inflammation. However, the mechanisms of immune suppression remain poorly understood. Here we report that murine NCC displays a lack of cell surface maturation markers in infiltrating myeloid cells. Furthermore, soluble parasite ligands (PL) failed to induce maturation of macrophages, and inhibited TLR-induced inflammatory cytokine production. Importantly, PL treatment abolished both LPS and thapsigargin-induced store operated Ca2+ entry (SOCE). Moreover, electrophysiological recordings demonstrated PL-mediated inhibition of LPS or Tg-induced currents that were TRPC1-dependent. Concomitantly STIM1-TRPC1 complex was also impaired that was essential for SOCE and sustained Ca2+ entry. Likewise loss of SOCE due to PL further inhibited NFkB activation. Overall, our results indicate that the negative regulation of agonist induced Ca2+ signaling pathway by parasite ligands may be a novel immune suppressive mechanism to block the initiation of the inflammatory response associated with helminth infections.
    Full-text · Article · Jul 2014 · PLoS ONE
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