Functional modulation of human macrophages through CD46 (measles virus receptor): production of IL-12 p40 and nitric oxide in association with recruitment of protein-tyrosine phosphatase SHP-1 to CD46.
Human CD46, formerly membrane cofactor protein, binds and inactivates complement C3b and serves as a receptor for measles virus (MV), thereby protecting cells from homologous complement and sustaining systemic measles infection. Suppression of cell-mediated immunity, including down-regulation of IL-12 production, has been reported on macrophages (Mphi) by cross-linking their CD46. The intracellular events responsible for these immune responses, however, remain unknown. In this study, we found that 6- to 8-day GM-CSF-treated peripheral blood monocytes acquired the capacity to recruit protein-tyrosine phosphatase SHP-1 to their CD46 and concomitantly were able to produce IL-12 p40 and NO. These responses were induced by stimulation with mAbs F(ab')(2) against CD46 that block MV binding or by a wild-type MV strain Kohno MV strain (KO; UV treated or untreated) that was reported to induce early phase CD46 down-regulation. Direct ligation of CD46 by these reagents, but not intracellular MV replication, was required for these cellular responses. Interestingly, the KO strain failed to replicate in the 6- to 8-day GM-CSF-cultured Mphi, while other MV strains replicated to form syncytia under the same conditions. When stimulated with the KO strain, rapid and transient dissociation of SHP-1 from CD46 was observed. These and previous results provide strong evidence that CD46 serves as a signal modulatory molecule and that the properties of ligands determine suppression or activation of an innate immune system at a specific maturation stage of human Mphi.
Kurita-Taniguchi
M
M
Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka, Japan.
Fukui
A
A
Hazeki
K
K
Hirano
A
A
Tsuji
S
S
Matsumoto
M
M
Watanabe
M
M
Ueda
S
S
Seya
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D001666:Binding Sites, Antibody; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D006224:Cricetinae; D015726:Giant Cells / Q000276:immunology / Q000821:virology; D006389:Hemagglutinins, Viral / Q000235:genetics / Q000276:immunology; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D008459:Measles virus / Q000276:immunology* / Q000502:physiology; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011991:Receptors, Virus / Q000276:immunology*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D013045:Species Specificity; D013997:Time Factors; D014162:Transfection; D014779:Virus Replication / Q000276:immunology; D018909:src Homology Domains / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C497857:CD46 protein, human; D006389:Hemagglutinins, Viral; D047908:Intracellular Signaling Peptides and Proteins; C497859:Mcp protein, mouse; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D011991:Receptors, Virus; C032397:hemagglutinin protein G, measles virus; D018664:Interleukin-12; D009569:Nitric Oxide; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases