Immunogenicity is preferentially induced in sparse dendritic cell cultures

Aikaterini Nasi,Vishnu Priya Bollampalli,Yang Chen,Bence Réthi,Liv Eidsmo,Susanne Nylén,Meng Sun,Antonio Gigliotti Rothfuchs,Sylvie Amu

doi:10.1038/srep43989

Aikaterini Nasi, Vishnu Priya Bollampalli + Show 7 more

Open Access

https://doi.org/10.1038/srep43989

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Abstract

We have previously shown that human monocyte-derived dendritic cells (DCs) acquired different characteristics in dense or sparse cell cultures. Sparsity promoted the development of IL-12 producing migratory DCs, whereas dense cultures increased IL-10 production. Here we analysed whether the density-dependent endogenous breaks could modulate DC-based vaccines. Using murine bone marrow-derived DC models we show that sparse cultures were essential to achieve several key functions required for immunogenic DC vaccines, including mobility to draining lymph nodes, recruitment and massive proliferation of antigen-specific CD4+ T cells, in addition to their TH1 polarization. Transcription analyses confirmed higher commitment in sparse cultures towards T cell activation, whereas DCs obtained from dense cultures up-regulated immunosuppressive pathway components and genes suggesting higher differentiation plasticity towards osteoclasts. Interestingly, we detected a striking up-regulation of fatty acid and cholesterol biosynthesis pathways in sparse cultures, suggesting an important link between DC immunogenicity and lipid homeostasis regulation.

Highlights

Dendritic cells (DCs) represent a heterogeneous group of antigen presenting cells that play an essential role in the initiation of the adaptive immune responses through inducing naive T cell activation in secondary lymphoid tissues
We have previously shown that lactic acid accumulates in dense human monocyte-derived DCs (MoDCs) cultures, and induces a cell concentration-dependent reprogramming of cytokine production and cell surface markers[16]
A group of fatty acid and retinoic acid biosynthesis genes were highly expressed in sparse cultures, which are all strictly regulated by a cholesterol-sensitive manner through transcription factors of the sterol regulatory element-binding protein (SREBP) family

Summary

Introduction

Dendritic cells (DCs) represent a heterogeneous group of antigen presenting cells that play an essential role in the initiation of the adaptive immune responses through inducing naive T cell activation in secondary lymphoid tissues. Previous findings have highlighted several mechanisms that contributed to DC vaccine efficiency including higher IL-12 production[3,4], efficient co-stimulatory signals[5], stronger induction of antigen-specific TH1 responses[6,7,8] or lower regulatory T cell numbers in the tumor tissue[6,9]. Other parameters, such as the site of injection, the number of injected DCs or the number of DCs reaching the T cell zone of lymph nodes are critical for DC vaccine efficiency[10,11,12]. The CD1a+/ CD1a− DC ratio varied greatly among blood donors, suggesting that a developmental heterogeneity might influence immunogenicity in individual DC vaccine preparations[14]

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