In vivo delivery of a microRNA-regulated transgene induces antigen-specific regulatory T cells and promotes immunologic tolerance.
We previously showed that incorporating target sequences for the hematopoietic-specific microRNA miR-142 into an antigen-encoding transgene prevents antigen expression in antigen-presenting cells (APCs). To determine whether this approach induces immunologic tolerance, we treated mice with a miR-142-regulated lentiviral vector encoding green fluorescent protein (GFP), and subsequently vaccinated the mice against GFP. In contrast to control mice, no anti-GFP response was observed, indicating that robust tolerance to the transgene-encoded antigen was achieved. Furthermore, injection of the miR-142-regulated vector induced a population of GFP-specific regulatory T cells. Interestingly, an anti-GFP response was observed when microRNA miR-122a was inserted into the vector and antigen expression was detargeted from hepatocytes as well as APCs. This demonstrates that, in the context of lentiviral vector-mediated gene transfer, detargeting antigen expression from professional APCs, coupled with expression in hepatocytes, can induce antigen-specific immunologic tolerance.
Annoni
Andrea
A
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.
Brown
Brian D
BD
Cantore
Alessio
A
Sergi
Lucia Sergi
LS
Naldini
Luigi
L
Roncarolo
Maria-Grazia
MG
D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000941:Antigens / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D018613:Microscopy, Confocal; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019076:Transgenes / Q000235:genetics / Q000276:immunology*
D000941:Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D035683:MicroRNAs; C529102:Mirn142 microRNA, mouse; D049452:Green Fluorescent Proteins