Human Regulatory T Cells Mediate Transcriptional Modulation of Dendritic Cell Function

被引:28
作者
Mavin, Emily [1 ]
Nicholson, Lindsay [1 ]
Ahmed, Syed Rafez [1 ]
Gao, Fei [2 ]
Dickinson, Anne [1 ]
Wang, Xiao-nong [1 ]
机构
[1] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
[2] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE7 1RU, Tyne & Wear, England
基金
英国惠康基金;
关键词
NF-KAPPA-B; GENE-EXPRESSION; DIFFERENTIATION; PHENOTYPE; LYMPHOCYTES; MACROPHAGES; SUPPRESSION; ACTIVATION; MATURATION; SURVIVAL;
D O I
10.4049/jimmunol.1502487
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-kappa B pathway, an upstream regulator of the aforementioned genes, concomitant with reduced expression of two NF-kappa B-signaling related genes RELB and NF kappa BIZ, 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-kB signaling pathway and upregulation of Wnt5a, suggesting Treg may interfere with DC reprogramming during maturation, thereby modulating DC function.
引用
收藏
页码:138 / 146
页数:9
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