Molecular assembly of CD46 with CD9, alpha3-beta1 integrin and protein tyrosine phosphatase SHP-1 in human macrophages through differentiation by GM-CSF.
Human CD46, formerly membrane cofactor protein (MCP), binds and inactivates complement C3b and serves as a receptor for measles virus (MV), thereby protecting cells from homologous complement and sustaining systemic viral infection. CD46 on activated macrophages (Mphi) but not intact monocytes is presumed to be the factor responsible for virus-mediated immune modulation including down-regulation of IL-12 production. As CD46 is expressed on both Mphi and monocytes, the molecular mechanisms responsible for these distinct immune responses remain largely unknown. Here, we found that peripheral blood monocytes treated for 5--8 days with GM-CSF (i.e. mature Mphi) acquired the capacity to assemble CD9, alpha3-beta1 integrin and the tyrosine phosphatase SHP-1 with their CD46. Prior to this maturation stage, Mphi expressed sufficient amounts of CD9 and CD46 but showed no such complex formation, and as in intact monocytes MV replication was markedly suppressed. By flow cytometry and confocal microscopy, the complex was found to assemble on the surface in cells treated with approximately 6 days with GM-CSF but not for approximately 2 days. Notably, an alternative MV receptor SLAM CDw150 was neither expressed nor recruited to this complex throughout GM-CSF-mediated Mphi differentiation. These responses and molecular links were not reproduced in the hamster cell line CHO expressing human CD46 although these cells acquired high susceptibility to MV. Based on these observations, MV susceptibility in human myeloid lineages appears not to be as simple as that observed in human CD46-transfected non-myeloid cells. The molecular complex involving CD46 may confer high MV permissiveness leading to immune modulation in Mphi.
Kurita-Taniguchi
Mitsue
M
Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka, Japan.
Hazeki
Kaoru
K
Murabayashi
Nozomu
N
Fukui
Aya
A
Tsuji
Shoutaro
S
Matsumoto
Misako
M
Toyoshima
Kumao
K
Seya
Tsukasa
T
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D016466:CHO Cells; D002454:Cell Differentiation / Q000187:drug effects; D006224:Cricetinae; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D039201:Integrin alpha3beta1; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000276:immunology / Q000378:metabolism*; D060245:Tetraspanin 29
D015703:Antigens, CD; C497857:CD46 protein, human; C554869:CD9 protein, human; D039201:Integrin alpha3beta1; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D060245:Tetraspanin 29; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; 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