Upregulation of PD-L1 on monocytes and dendritic cells by HIV-1 derived TLR ligands.
ABSTRACT Increased PD-L1 expression has been reported in HIV-1-infected individuals, but the mechanisms leading to PD-L1 upregulation remain to be elucidated. Here we demonstrate that HIV-1-derived Toll-like receptor (TLR)7/8 ligands can induce MyD88-dependent upregulation of PD-L1 on plasmacytoid dendritic cells, myeloidic dendritic cells and monocytes. These data suggest a mechanism through which HIV-1-derived TLR ligands might contribute to the functional impairment of virus-specific PD-1-positive T cells by inducing the upregulation of PD-L1 on antigen-presenting cells.
Full-textDOI: · Available from: Mark Brockman, Mar 22, 2014
- SourceAvailable from: Joeri L Aerts
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- "Monocytes and CCR5 + T cells from HIV-uninfected persons up-regulate PD-L1, but not PD- L2, upon in vitro exposure to HIV, through a mechanism involving IFN-. Another mechanism for the increased expression of PD-L1 during HIV infection could be the presence of HIV-derived TLR 7/8 ligands . CD14 + cells and mDCs in the lymph "
ABSTRACT: HIV infection is characterized by a number of abnormalities in several components of the immune system. For example, during HIV infection, a massive decrease of CD4(+) T cells is observed, as well as a progressive depletion of naïve CD8(+) T cells. Furthermore, elevated numbers of apoptotic B and T cells are present in HIV-infected patients, and a systemic immune activation results in T-cell exhaustion. Finally, HIV infection is characterized by the presence of functionally impaired dendritic cells, with decreased expression of maturation markers, decreased secretion of cytokines and defects in antigen processing and presentation. All these characteristics result in the occurrence of non-functional cytotoxic T lymphocytes, that fail to control HIV-replication in most individuals during progressive disease. Costimulatory and co-inhibitory molecules are involved in the activation, differentiation and survival of several cell-types of the immune system. Each costimulatory receptor (generally expressed on effector cells) can conjugate with one or more specific ligands (expressed on antigen-presenting cells), which leads to an activation of intracellular signaling pathways inside the cells on which they are expressed. HIV infection is characterized by an aberrant expression of these molecules on cells of the immune system. Many of the immune deficiencies mentioned in the previous paragraph can be explained by abnormal expression of costimulatory molecules, and could consequently be overcome by interfering with their interactions. In this review, we give an overview of the functions and expression patterns of the receptor/ligand pairs of the tumor necrosis factor and the B7 super-families of costimulatory and co-inhibitory molecules in HIV-infected patients. We will also discuss possibilities for manipulating their signaling as a therapeutic anti-HIV tool.Current Molecular Medicine 03/2011; 11(3):172-96. DOI:10.2174/1566211213754945240 · 3.61 Impact Factor
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- "It was also reported that in HIV-1 infected individuals upregulation of PD-L1 is one mechanism of T cell inhibition. The same study also showed that HIV-1-derived TLR7/8 ligands are able to increase MyD88-dependent PD- L1 expression on monocytes, dendritic cells and myeloid dendritic cells (Meier et al., 2008). We confirmed this finding, and observed PD-L1 upregulation on monocytes upon treatment with TLR7/8 ORN agonists. "
ABSTRACT: Toll-like receptors (TLRs) are mediators of innate immune responses detecting conserved pathogen-associated molecules. Whereas most TLRs are expressed on the cell surface, TLR3, 7, 8 and 9 are predominantly localized in endosomal compartments. Recent studies reported that TLRs are also expressed by T lymphocytes, resulting in direct co-stimulation of isolated CD4(+) T cells for example by Pam3CSK4 (TLR2 ligand) or flagellin (TLR5 ligand). We here describe enhanced IFN-γ production and T cell proliferation by anti-CD3 T cell receptor (TCR) or antigenic stimulation of purified human CD4(+) T cells upon co-culture with TLR7/8 specific single-stranded oligoribonucleotides or small molecule ligands. Surprisingly, TLR7/8 stimulation of CD4(+) T cells within a whole peripheral mononuclear cell (PBMC) environment did not result in enhanced T cell proliferation, but in a lack of proliferation that was cell-cell contact dependent. Immune cell depletion assays pointed towards a monocyte-mediated effect. Different TLR ligands influenced T cell proliferation differently. The effect of inhibition of T cell proliferation was most prominently seen for TLR7 ligands whereas the effects were minimal for TLR8 and TLR9 ligands indicating that the suppressive phenotype is unique only for certain TLRs. Our results strongly suggest that co-stimulation of T cell proliferation by TLR7/8 agonists is dependent on the specific cellular context.Immunobiology 01/2010; 216(1-2):12-23. DOI:10.1016/j.imbio.2010.03.011 · 3.18 Impact Factor
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ABSTRACT: Lymph nodes (LNs) represent the principal site where antigen-specific memory T- and B-cell responses are primed and differentiated into memory and effector cells. During chronic viral infections such as HIV, these lymphoid tissues undergo substantial structural changes. These changes are mostly caused by an imbalanced cytokine milieu, hyper-immune activation and collagen deposition leading to fibrotic LNs. The structural integrity of the LNs is essential to prime and maintain memory responses. Because cellular signalling events both up- and down-stream of FOXO3a are critical to the generation and the maintenance of lymphocyte memory, this review will focus on the interplay between the deregulation of the immune system caused by the virus and its impact on FOXO3a.Seminars in Immunology 07/2008; 20(3):196-203. DOI:10.1016/j.smim.2008.07.008 · 6.12 Impact Factor