The non-classical MHC molecule HLA-G protects human muscle cells from immune-mediated lysis: implications for myoblast transplantation and gene therapy.
HLA-G is a non-classical MHC class I molecule with highly limited tissue distribution which has been attributed chiefly immune-regulatory functions. We previously have reported that HLA-G is expressed in inflamed muscle in vivo and by cultured myoblasts in vitro. Here, we used the in vitro models of human myoblasts or TE671 muscle rhabdomyosarcoma cells to characterize the functional role of HLA-G for muscle immune cell interactions. Gene transfer of the two major isoforms of HLA-G (transmembranous HLA-G1 and soluble HLA-G5) into TE671 rendered these cells resistant to alloreactive lysis by direct inhibition of natural killer (NK) cells, and CD4 and CD8 T cells. Further, HLA-G reduced alloproliferation, interfered with effective priming of antigen-specific cytotoxic T cells and reduced antigen-specific alloreactive lysis. HLA-G pre-induced on cultured myoblasts inhibited lysis by alloreactive peripheral blood mononuclear cells. This protection was reversed by a neutralizing HLA-G antibody. Interestingly, a few HLA-G-positive cells within a population of HLA-G-negative muscle target cells conveyed significant inhibitory effects on alloreactive lysis. Our results reveal further insights into the immunobiology of muscle and suggest that ectopic expression of HLA-G may promote the survival of transplanted myoblasts in the future treatment of hereditary muscle diseases. Further, HLA-G could represent a novel self-derived anti-inflammatory principle applicable in strategies against inflammatory aggression.
Wiendl
Heinz
H
Department of Neurology, University of Tübingen, Medical School, Tübingen, Germany. heinz.wiendl@uni-tuebingen.de
Mitsdoerffer
Meike
M
Hofmeister
Valeska
V
Wischhusen
Joerg
J
Weiss
Elisabeth H
EH
Dichgans
Johannes
J
Lochmuller
Hanns
H
Hohlfeld
Reinhard
R
Melms
Arthur
A
Weller
Michael
M
D017209:Apoptosis / Q000276:immunology; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D002460:Cell Line; D006680:HLA Antigens / Q000235:genetics / Q000502:physiology*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D032446:Myoblasts / Q000276:immunology* / Q000637:transplantation; D009220:Myositis / Q000276:immunology*; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I