title: HLA-G expression levels influence the tolerogenic activity of human DC-10.
abstract: Human leukocyte antigen (HLA)-G is a non-classical HLA class I molecule with known immune-modulatory functions. Our group identified a subset of human dendritic cells, named DC-10, that induce adaptive interleukin-10-producing T regulatory type 1 (Tr1) cells via the interleukin-10-dependent HLA-G/ILT4 pathway. In this study we aimed at defining the role of HLA-G in DC-10-mediated Tr1 cell differentiation. We analyzed phenotype, functions, and genetic variations in the 3' untranslated region of the HLA-G locus of in vitro-differentiated DC-10 from 67 healthy donors. We showed that HLA-G expression on DC-10 is donor-dependent. Functional studies demonstrated that DC-10, independently of HLA-G expression, secrete interleukin-10 and negligible levels of interleukin-12. Interestingly, DC-10 with high HLA-G promote allo-specific anergic T cells that contain a significantly higher frequency of Tr1 cells, defined as interleukin-10-producing (P=0.0121) or CD49b(+)LAG-3(+) (P=0.0031) T cells, compared to DC-10 with low HLA-G. We found that the HLA-G expression on DC-10 is genetically imprinted, being associated with specific variations in the 3' untranslated region of the gene, and it may be finely tuned by microRNA-mediated post-transcriptional regulation. These data highlight the important role of HLA-G in boosting DC-10 tolerogenic activity and confirm that interleukin-10 production by DC-10 is necessary but not sufficient to promote Tr1 cells at high frequency. These new insights into the role of HLA-G in DC-10-mediated induction of Tr1 cells provide additional information for clinical use in Tr1- or DC-10-based cell therapy approaches.
authors: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy.
authors: Giada
authors: G
authors: Amodio
authors: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy Ph.D Program in Translational and Molecular Medicine (DIMET), University of Milan-Bicocca, Italy.
authors: Michela
authors: M
authors: Comi
authors: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Daniela
authors: D
authors: Tomasoni
authors: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy Department of Public Health and Cell Biology, Tor Vergata University, Rome, Italy.
authors: Monica Emma
authors: ME
authors: Gianolini
authors: Department of Medical Sciences, Section of Microbiology, University of Ferrara, Italy.
authors: Roberta
authors: R
authors: Rizzo
authors: Service de Recherches en Hémato-Immunologie, CEA-DSV-DRM, Hôpital Saint-Louis, IUH, Paris, France.
authors: Joël
authors: J
authors: LeMaoult
authors: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy.
authors: Maria-Grazia
authors: MG
authors: Roncarolo
authors: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy gregori.silvia@hsr.it.
authors: Silvia
authors: S
authors: Gregori
mesh_terms: D020413:3' Untranslated Regions; D000483:Alleles; D002454:Cell Differentiation; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D059951:HLA-G Antigens / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D016130:Immunophenotyping; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D016207:Cytokines; D059951:HLA-G Antigens; C550856:MIRN152 microRNA, human; D008562:Membrane Glycoproteins; D035683:MicroRNAs