Maturation of antigen-presenting cells is compromised in HLA-G transgenic mice.
The human MHC class Ib antigen HLA-G is thought to regulate maternal immune responses during pregnancy. Here we show that expression of HLA-G in transgenic mice diminished cellular immunity by inhibiting maturation of myelomonocytic cells into functional antigen-presenting cells (APC). Skin allografts applied to HLA-G transgenic mice survived longer and resultant T cell responses were less potent compared to control mice. T cells from HLA-G mice responded normally to allogeneic APC and immunohistological analyses of spleen revealed no marked abnormalities. However, spontaneous outgrowths of myeloid cells were observed when bone marrow or splenocytes from HLA-G mice were cultured in vitro, but functionally competent APC did not develop spontaneously in bone marrow cultures supplemented with granulocyte macrophage colony stimulating factor (GM-CSF). Addition of lipopolysaccharide (LPS) to GM-CSF-derived bone marrow cultures rescued APC maturation. Studies using HLA-G tetrameric reagents revealed that HLA-G-specific binding activity was associated with CD11c(+) myelomonocytic cells, while binding to lymphoid and NK cell subsets was undetectable. These data show that spontaneous maturation of functionally competent dendritic cells (DC) is compromised in HLA-G mice. We hypothesize that HLA-G inhibits maturation of DC via receptor-mediated interactions with myelomonocytic precursors, which render immature DC precursors unable to receive signals from activated T cells.
Horuzsko
A
A
Program in Molecular Immunology, Department of Medicine, Medical College of Georgia, Augusta, GA 30912, USA.
Lenfant
F
F
Munn
D H
DH
Mellor
A L
AL
D000818:Animals; D000938:Antigen-Presenting Cells / Q000473:pathology*; D001704:Biopolymers; D001854:Bone Marrow Cells / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000473:pathology; D006085:Graft Survival; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006680:HLA Antigens / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000737:chemistry; D007111:Immunity, Cellular; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D017510:Protein Folding; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016038:Skin Transplantation / Q000276:immunology; D013154:Spleen / Q000473:pathology; D014184:Transplantation, Homologous / Q000276:immunology; D001613:beta 2-Microglobulin / Q000737:chemistry
D001704:Biopolymers; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D006657:Histones; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D001613:beta 2-Microglobulin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor