title: Phagocytosis, a potential mechanism for myeloid-derived suppressor cell regulation of CD8+ T cell function mediated through programmed cell death-1 and programmed cell death-1 ligand interaction.
abstract: CD8(+) T cells become exhausted, inducing cell surface protein programmed cell death-1 (PD-1) as chronic virus diseases or tumors progress, but underlying mechanisms of this are unclear. We previously showed that M-CSF is important for developing tolerogenic dendritic cells (DCs) from human CD14(+) monocytes. In this article, we identify M-CSF-derived DCs (M-DCs) after stimulation with IL-10 as myeloid-derived suppressor cells with additional tolerogenic activities to CD8(+) T cells. IL-10 increased PD-1 ligand expression on M-DC, and IL-10-stimulated M-DCs (M-DC/IL-10) induced expression of PD-1 on, and apoptosis of, CD8(+) T cells and phagocytosed CD8(+) T cells. Enhanced phagocytic activity of M-DC/IL-10 required IFN-γ, which further increased PD-1 ligand and PD-2 ligand expression on M-DC/IL-10. IFN-γ-stimulated M-DC/IL-10 cells were phenotypically macrophage-like cells with little or no expression of CD86, a costimulatory molecule, but with high expression levels of CD14, CD200R, and CD80. No phagocytic activity was detected with GM-CSF-derived DCs. We propose that phagocytosis by IFN-γ-stimulated M-DC/IL-10 cells, which may be DCs or, alternatively, a unique subset of macrophages, may be a mechanism by which IFN-γ-producing CD8(+) T cells are tolerized after type 1 immune responses to chronic virus or tumor, and that IFN-γ links effector CD8(+) T cells to their phagocytic clearance.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. yjkim@iupui.edu
authors.forename: Young-June
authors.initials: YJ
authors.lastname: Kim
authors.forename: Su-Jung
authors.initials: SJ
authors.lastname: Park
authors.forename: Hal E
authors.initials: HE
authors.lastname: Broxmeyer
mesh_terms: D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D008024:Ligands; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology; D018613:Microscopy, Confocal; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D008024:Ligands; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016753:Interleukin-10; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma