Identification of a Novel OX40L+ Dendritic Cell Subset That Selectively Expands Regulatory T cells

Alejandra Marinelarena,Prabhakaran Kumar,Ajay V Maker,Palash Bhattacharya,Bellur S Prabhakar

doi:10.1038/s41598-018-33307-z

Alejandra Marinelarena, Prabhakaran Kumar + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-33307-z

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Abstract

We have previously shown GM-CSF derived bone-marrow dendritic cells (G-BMDCs) can induce the selective expansion of Tregs through the surface-bound molecule OX40L; however, the physiological role of this ex vivo derived DC subset remained to be elucidated. We determined GM-CSF administration to mice induced the generation of in vivo derived OX40L+ DCs, phenotypically similar to ex vivo OX40L+G-BMDCs, in the spleen, brachial lymph nodes and liver. The generation of OX40L+ DCs correlated with increased percentages of functionally suppressive Tregs in the spleen, brachial lymph nodes, and liver of GM-CSF treated mice. DCs from GM-CSF treated mice expanded Tregs in CD4+ T-cell co-cultures in an OX40L dependent manner, suggesting OX40L+ DCs may play a role in peripheral Treg homeostasis. Furthermore, comparing the transcriptome data of OX40L+ DCs to that of all immune cell types revealed OX40L+ DCs to be distinct from steady-state immune cells and, microarray analysis of OX40L+G-BMDCs and OX40L−G-BMDCs revealed higher expression of molecules that are associated with tolerogenic phenotype and could play important roles in the function of OX40L+ DCs. These findings suggest that OX40L+ DCs may represent a unique DC subset induced under inflammatory conditions that may play an essential role in maintaining Treg homeostasis.

Highlights

Since the depletion of DCs can lead to autoimmune pathologies, it has been postulated that increasing DC populations could restore tolerance and prevent autoimmunity
While we observed a significant decrease in Treg proliferation in the presence of OX40L− granulocyte macrophage colony-stimulating factor (GM-CSF) derived bone-marrow dendritic cells (G-bone-marrow derived DCs (BMDCs)) relative to bulk G-BMDCs, we observed a further increase in Treg proliferation when CD4+ T-cells were co-cultured with OX40L+G-BMDCs, implicating the significant role of OX40L expressed on CD11c+ cells in the selective Treg expansion (Fig. 1A,B)
Our study suggests that OX40L+ G-BMDCs can be induced in vivo upon GM-CSF administration and may represent a non-steady state DC subtype involved in Treg homeostasis and immunosuppression

Summary

Introduction

Since the depletion of DCs can lead to autoimmune pathologies, it has been postulated that increasing DC populations could restore tolerance and prevent autoimmunity. Subsequent studies discovered that ex vivo derived DCs, generated from bone marrow (BM) precursor cells isolated from WT or MHC Class-II−/− mice differentiated in the presence of GM-CSF (G-BMDCs), could selectively expand Foxp3+ Tregs in a cell-to-cell-contact dependent manner, independent of TCR-signaling, but most importantly, dependent on the DC cell surface expression of OX40L15,16. OX40L, a member of the tumor necrosis factor superfamily, has been strongly implicated in the proliferation and survival of T cells by playing a critical role as a co-stimulatory molecule in association with T-cell receptor engagement[17,18] Expression of this molecule has been detected on antigen presenting cells, such as dendritic cells[19], B-cells[20], and macrophages[21], but can be induced on various other immune cell types such as mast cells[22,23], natural killer cells[24], and vascular endothelial cells[25]. Our data suggest that OX40L+ DCs may represent a non-steady-state myeloid DC subtype involved in Treg expansion in vivo and point to a hitherto undiscovered mechanism of Treg homeostasis under inflammatory conditions where GM-CSF levels are expected to be much higher

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