title: Macrophages and Myeloid Dendritic Cells Lose T Cell-Stimulating Function in Simian Immunodeficiency Virus Infection Associated with Diminished IL-12 and IFN-α Production.
abstract: Impaired T cell responses are a defining characteristic of HIV infection, but the extent to which altered mononuclear phagocyte function contributes to this defect is unclear. We show that mononuclear phagocytes enriched from rhesus macaque lymph nodes have suppressed ability to stimulate CD4 T cell proliferation and IFN-γ release after acute SIV infection. When individual populations were isolated, myeloid dendritic cells (mDC) and macrophages but not plasmacytoid DC (pDC) had suppressed capacity to stimulate CD4 T cell proliferation, with macrophage function declining as infection progressed. Macrophages, but not pDC or mDC, had suppressed capacity to induce IFN-γ release from CD4 T cells in acute infection, even after stimulation with virus-encoded TLR7/8 ligand. Changes in expression of costimulatory molecules did not explain loss of function postinfection. Conversely, pDC and mDC had marked loss of IFN-α and IL-12 production, respectively, and macrophages lost production of both cytokines. In T cell cocultures without TLR7/8 ligand, macrophages were the primary source of IL-12, which was profoundly suppressed postinfection and correlated with loss of IFN-γ release by T cells. TLR7/8-stimulated pDC, mDC and macrophages all produced IL-12 in T cell cocultures, which was suppressed in chronic infection. Supplementing IL-12 enhanced mDC-driven IFN-γ release from T cells, and IL-12 and IFN-α together restored function in TLR7/8-activated macrophages. These findings reveal loss of macrophage and mDC T cell-stimulating function in lymph nodes of SIV-infected rhesus macaques associated with diminished IL-12 and IFN-α production that may be a factor in AIDS immunopathogenesis.
authors: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15213; Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15213;
authors: Elizabeth R
authors: ER
authors: Wonderlich
authors: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15213; and.
authors: Wen-Chi
authors: WC
authors: Wu
authors: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15213; and.
authors: Daniel P
authors: DP
authors: Normolle
authors: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15213; Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15213; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213 smbb@pitt.edu.
authors: Simon M
authors: SM
authors: Barratt-Boyes
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D016898:Interferon-alpha / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008253:Macaca mulatta; D008264:Macrophages / Q000276:immunology*; D008297:Male; D010587:Phagocytosis / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000276:immunology; D051200:Toll-Like Receptor 8 / Q000276:immunology
chemical_list: D016898:Interferon-alpha; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D018664:Interleukin-12