Transcriptional and functional characterization of CD137L-dendritic cells identifies a novel dendritic cell phenotype.

Zulkarnain Harfuddin,Kaibo Duan,Siew Cheng Wong,Michael Poidinger,Bhushan Dharmadhikari,Herbert Schwarz,Shaqireen Kwajah

doi:10.1038/srep29712

Abstract

The importance of monocyte-derived dendritic cells (DCs) is evidenced by the fact that they are essential for the elimination of pathogens. Although in vitro DCs can be generated by treatment of monocytes with GM-CSF and IL-4, it is unknown what stimuli induce differentiation of DCs in vivo. CD137L-DCs are human monocyte-derived DC that are generated by CD137 ligand (CD137L) signaling. We demonstrate that the gene signature of in vitro generated CD137L-DCs is most similar to those of GM-CSF and IL-4-generated immature DCs and of macrophages. This is reminiscent of in vivo inflammatory DC which also have been reported to share gene signatures with monocyte-derived DCs and macrophages. Performing direct comparison of deposited human gene expression data with a CD137L-DC dataset revealed a significant enrichment of CD137L-DC signature genes in inflammatory in vivo DCs. In addition, surface marker expression and cytokine secretion by CD137L-DCs resemble closely those of inflammatory DCs. Further, CD137L-DCs express high levels of adhesion molecules, display strong attachment, and employ the adhesion molecule ALCAM to stimulate T cell proliferation. This study characterizes the gene expression profile of CD137L-DCs, and identifies significant similarities of CD137L-DCs with in vivo inflammatory monocyte-derived DCs and macrophages.

Highlights

Monocyte-derived dendritic cells are critical to a robust anti-pathogen immune response
Multivariate transcriptome analysis indicates a close relationship of CD137L-DCs are induced by a signal (CD137) ligand (CD137L)-dendritic cells (DCs) with in vitro generated immature cDCs and macrophages
We conclude that the transcriptome profile of CD137L-DCs is unique and partly resembles the profiles of immature cDCs (imm cDC) and macrophages

Summary

Introduction

Monocyte-derived dendritic cells (moDC) are critical to a robust anti-pathogen immune response. MoDCs can be generated by treatment of monocytes with GM-CSF and IL-4, and are considered to represent in vivo DCs that appear during infection or inflammation[3]. A sub-set of epidermal DCs has been shown to appear during atopic eczema with implications in skin inflammation[8] These DC subsets have been reported to have considerably different gene expression profiles when compared to the moDCs generated in vitro by treatment with GM-CSF and IL-4 (referred to as cDC forth)[9]. A number of studies have shown objective clinical responses, the overall clinical benefits are low These disappointing results are largely due the inability of cDCs to mount sufficiently strong T cell responses[11,12]. Transcriptome analysis of primary DC subsets from man and mouse has helped to determine the extent of homology between the two species, and to classify conserved DC populations[9,17]

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Results

Conclusion