title: DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK-T cell interaction.
abstract: An important role for natural killer (NK) cells in the regulation of T-cell responses is emerging, although the receptor pairs regulating the NK-T-cell interaction have still not been identified. We found that superantigen-stimulated T cells express Nectin-2 (CD112) and poliovirus receptor (PVR; CD155), the ligands of the activating NK receptor DNAX accessory molecule-1 (DNAM-1; CD226). Interestingly, only PVR was present at the T cell surface, particularly on cells in the S and G(2)/M phases of the cell cycle. The up-regulation of PVR expression involves DNA-damage response (DDR)-dependent pathways, because we found that pharmacologic inhibition of ATM and ATR kinases reduced PVR expression and that PVR was almost exclusively induced on cells expressing the DDR marker γH2AX. Oxidative stress contributed to DDR activation, and our results showed impaired PVR levels in the presence of the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC), being monocytes the main ROS source needed for optimal PVR expression on activated T cells. Interestingly, in accordance with ligand expression, NK cells lysed allogeneic proliferating more efficiently than nonproliferating T lymphocytes, with a mechanism requiring the cooperation between DNAM-1 and NKG2D. These results could contribute to unraveling the role of NK cells in the down-regulation of T-cell responses in physiologic and pathologic processes such as autoimmunity or GVHD.
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Ardolino
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zingoni
authors.forename: Cristina
authors.initials: C
authors.lastname: Cerboni
authors.forename: Francesca
authors.initials: F
authors.lastname: Cecere
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soriani
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Iannitto
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D004249:DNA Damage; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D000075983:Nectins; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011991:Receptors, Virus / Q000096:biosynthesis / Q000235:genetics; D018089:Superantigens / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C527085:KLRK1 protein, human; D018950:Lipopolysaccharide Receptors; D055655:NK Cell Lectin-Like Receptor Subfamily K; D000075983:Nectins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011991:Receptors, Virus; D018089:Superantigens; D025521:Tumor Suppressor Proteins; C066100:poliovirus receptor; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases