Antigen mRNA-transfected, allogeneic fibroblasts loaded with NKT-cell ligand confer antitumor immunity.
The maturation of dendritic cells (DCs) in situ by danger signals plays a central role in linking innate and adaptive immunity. We previously demonstrated that the activation of invariant natural killer T (iNKT) cells by administration of alpha-galactosylceramide (alpha-GalCer)-loaded tumor cells can act as a cellular adjuvant through the DC maturation. In the current study, we used allogeneic fibroblasts loaded with alpha-GalCer and transfected with antigen-encoding mRNA, thus combining the adjuvant effects of iNKT-cell activation with delivery of antigen to DCs in vivo. We found that these cells produce antigen protein and activate NK and iNKT cells. When injected into major histocompatibility complex (MHC)-mismatched mice, they elicited antigen-specific T-cell responses and provided tumor protection, suggesting that these immune responses depend on host DCs. In addition, antigen-expressing fibroblasts loaded with alpha-GalCer lead to a more potent T-cell response than those expressing NK cell ligands. Thus, glycolipid-loaded, mRNA-transfected allogeneic fibroblasts act as cellular vectors to provide iNKT-cell activation, leading to DC maturation and T-cell immunity. By harnessing the innate immune system and generating an adaptive immune response to a variety of antigens, this unique tool could prove clinically beneficial in the development of immunotherapies against malignant and infectious diseases.
Fujii
Shin-ichiro
S
Research Unit for Cellular Immunotherapy, The Institute of Physical and Chemical Research (RIKEN), Research Center for Allergy and Immunology, Yokohama, Japan. fujiis@rcai.riken.jp
Goto
Akira
A
Shimizu
Kanako
K
D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000276:immunology*; D005699:Galactosylceramides / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007109:Immunity; D007111:Immunity, Cellular; D019746:Intramolecular Oxidoreductases / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection; D014611:Vaccination
D055610:Antigens, CD1d; D000951:Antigens, Neoplasm; D005699:Galactosylceramides; D015395:Histocompatibility Antigens Class I; D012333:RNA, Messenger; C493154:alpha-galactosylceramide; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase