title: Human Regulatory T Cells Mediate Transcriptional Modulation of Dendritic Cell Function.
abstract: Regulatory T cells (Treg) attenuate dendritic cell (DC) maturation and stimulatory function. Current knowledge on the functional impact of semimature DC is limited to CD4+T cell proliferation and cytokine production. Little is known about the molecular basis underpinning the functional effects of Treg-treated DC (Treg-DC). We present novel evidence that Treg-DC skewed CD4+naive T cell polarization toward a regulatory phenotype and impaired CD8+T cell allo-reactive responses, including their ability to induce target tissue damage in a unique in vitro human graft-versus-host disease skin explant model. Microarray analysis clustered Treg-DC as a discrete population from mature-DC and immature-DC, with 51 and 93 genes that were significantly over- or underexpressed, respectively, compared with mature-DC. Quantitative real-time PCR analysis revealed an intermediate expression level of CD38, CD83, CD80 and CD86 mRNA in Treg-DC, lower than mature-DC, higher than immature-DC. We also observed an attenuation of NF-κB pathway, an upstream regulator of the aforementioned genes, concomitant with reduced expression of two NF-κB-signaling related genes RELB and NFκBIZ, in the Treg-DC, together with an increased expression of Wnt5a, a negative regulator of DC differentiation. We further confirmed that the Treg-DC-mediated skewed CD4+naive T cell polarization resulted from decreased IL-12 secretion by Treg-DC, which may be post-transcriptionally modulated by decreased expression of microRNA-155 in Treg-DC. To our knowledge, this is the first study demonstrating a transcriptional modulation of DC function by human Treg, partially via attenuation of the NF-κB signaling pathway and upregulation of Wnt5a, suggesting Treg may interfere with DC reprogramming during maturation, thereby modulating DC function.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom; and.
authors.forename: Emily
authors.initials: E
authors.lastname: Mavin
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom; and.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Nicholson
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom; and.
authors.forename: Syed
authors.identifier: 0000-0002-2132-9011
authors.initials: S
authors.lastname: Rafez Ahmed
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE7 1RU, United Kingdom.
authors.forename: Fei
authors.identifier: 0000-0003-1797-0479
authors.initials: F
authors.lastname: Gao
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom; and.
authors.forename: Anne
authors.identifier: 0000-0002-7356-7636
authors.initials: A
authors.lastname: Dickinson
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom; and X.N.Wang@ncl.ac.uk.
authors.forename: Xiao-Nong
authors.initials: XN
authors.lastname: Wang
mesh_terms: D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014158:Transcription, Genetic; D000071818:Wnt-5a Protein / Q000276:immunology / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D000071818:Wnt-5a Protein