Receptor engagement on cells expressing a ligand for the tolerance-inducing molecule OX2 induces an immunoregulatory population that inhibits alloreactivity in vitro and in vivo.
Increased survival of C57BL/6 renal allografts following portal vein donor-specific pretransplant immunization of C3H mice is associated with increased expression of the molecule OX2 seen on host dendritic cells, along with a marked polarization in cytokine production from lymphocytes harvested from the transplanted animals, with preferential production of IL-4, IL-10, and TGF-beta on donor-specific restimulation in vitro, and decreased production of IL-2, IFN-gamma, and TNF-alpha compared with non-portal vein-immunized control transplanted mice. The increased renal allograft survival and the altered cytokine production are abolished by infusion of anti-mouse OX2 mAb (3B6). Infusion of a soluble OX2:Fc immunoadhesin can itself produce significant prolongation of xeno- and allografts in mice. We have used FITC-conjugated OX2:Fc to characterize cells expressing a ligand (OX2L) for OX2, and provide evidence that subpopulations of LPS-stimulated splenic macrophages, Con A-activated splenic T cells, and the majority (>80%) of gammadeltaTCR(+) T cells express this ligand. We show below that F4/80(+), OX2L(+) splenic macrophages, admixed with OX2:Fc, represent a potent immunosuppressive population capable of causing more profound inhibition of alloreactivity in vitro or in vivo than that seen using either OX2:Fc or OX2(+) (or OX2L(+)) cells alone. Immunoregulation by this OX2L(+) population occurs in an MHC-restricted fashion.
Gorczynski
R M
RM
University Health Network, Toronto, Canada.
Yu
K
K
Clark
D
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D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD; D000954:Antigens, Surface / Q000096:biosynthesis / Q000378:metabolism*; D001666:Binding Sites, Antibody / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D006650:Histocompatibility Testing; D007108:Immune Tolerance / Q000235:genetics; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology* / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D000954:Antigens, Surface; D007141:Immunoglobulin Fc Fragments; D007519:Isoantigens; D008024:Ligands; D008070:Lipopolysaccharides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011993:Recombinant Fusion Proteins; D016650:Fluorescein-5-isothiocyanate; C042739:antigens, CD200