Differential transcriptome of tolerogenic versus inflammatory dendritic cells points to modulated T1D genetic risk and enriched immune regulation

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Abstract

Tolerogenic dendritic cells (tolDCs) are assessed as immunomodulatory adjuvants to regulate autoimmunity. The underlying gene expression endorsing their regulatory features remains ill-defined. Using deep mRNA sequencing, we compared transcriptomes of 1,25-dihydroxyvitaminD3/dexametasone-modulated tolDCs with that of non-modulated mature inflammatory DCs (mDCs). Differentially expressed genes controlled cellular interactions, metabolic pathways and endorse tolDCs with the capacity to regulate cell activation through nutrient and signal deprivation, collectively gearing tolDCs into tolerogenic immune regulators. Gene expression differences correlated with protein expression, designating low CD86 and high CD52 on the cell surface as superior discriminators between tolDCs and mDCs. Of 37 candidate genes conferring risk to developing type 1 diabetes (T1D), 11 genes differentially expressed in tolDCs and mDCs regulated immune response and antigen-presenting activity. Differential-expressed transcripts of candidate risk loci for T1D suggest a role of these ‘risk genes’ in immune regulation, which targeting may modulate the genetic contribution to autoimmunity.

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Acknowledgements

This work was supported by European Union 7th Framework Programme (FP7/2007–2013) Grant 241447 (NAIMIT) and the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement 115797 (INNODIA) (this Joint Undertaking receives support from the Union’s Horizon 2020 research and innovation program and ‘EFPIA,’ ‘JDRF,’ and ‘The Leona M. and Harry B. Helmsley Charitable Trust.’), Netherlands Organization for Scientific Research Vici Grant 918.86.611, the Dutch Arthritis Foundation (LLP16) and by an Expert Center Grant from the Dutch Diabetes Research Foundation.

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Correspondence to T Nikolic.

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Supplementary Information accompanies this paper on Genes and Immunity website

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