Dendritic cell-secreted lipocalin2 induces CD8+ T-cell apoptosis, contributes to T-cell priming and leads to a TH1 phenotype.

Melanie Floderer,Michaela Prchal-Murphy,Caterina Vizzardelli,Silke Appel

doi:10.1371/journal.pone.0101881

Melanie Floderer, Michaela Prchal-Murphy + Show 2 more

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https://doi.org/10.1371/journal.pone.0101881

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Abstract

Lipocalin 2 (LCN2), which is highly expressed by dendritic cells (DCs) when treated with dexamethasone (Dex) and lipopolysaccharide (LPS), plays a key role in the defence against bacteria and is also involved in the autocrine apoptosis of T-cells. However, the function of LCN2 when secreted by DCs is unknown: this is a critical gap in our understanding of the regulation of innate and adaptive immune systems. Tolerance, stimulation and suppression are functions of DCs that facilitate the fine-tuning of the immune responses and which are possibly influenced by LCN2 secretion. We therefore examined the role of LCN2 in DC/T-cell interaction. WT or Lcn2−/− bone marrow-derived DCs were stimulated with LPS or LPS+IFN-γ with and without Dex and subsequently co-cultured with T-cells from ovalbumin-specific TCR transgenic (OT-I and OT-II) mice. We found that CD8+ T-cell apoptosis was highly reduced when Lcn2−/− DCs were compared with WT. An in vivo CTL assay, using LPS-treated DCs, showed diminished killing ability in mice that had received Lcn2−/− DCs compared with WT DCs. As a consequence, we analysed T-cell proliferation and found that LCN2 participates in T-cell-priming in a dose-dependent manner and promotes a TH1 microenvironment. DC-secreted LCN2, whose function has previously been unknown, may in fact have an important role in regulating the balance between TH1 and TH2. Our results yield insights into DC-secreted LCN2 activity, which could play a pivotal role in cellular immune therapy and in regulating immune responses.

Highlights

Dendritic cells (DCs) are professional antigen-presenting cells that coordinate innate and adaptive immune responses [1]
Lipocalin 2 (LCN2) is not affecting DC maturation LCN2 is widely expressed by epithelial cells, fibroblasts, macrophages, T-cells [23] and DCs [19], and it is present in the uterus during involution, a period of extensive apoptosis [22]
We observed a delayed up-regulation of MHC class II during the first 6 hours in the Lcn22/2 DCs, which reached a similar level in WT and Lcn22/2 DCs after 24 hours

Summary

Introduction

Dendritic cells (DCs) are professional antigen-presenting cells that coordinate innate and adaptive immune responses [1] They are the major source of cytokines, which can modulate effector cells. Because of these remarkable properties, DCs are valuable tools when developing vaccination strategies against tumours [2]. When DCs encounter danger signals, such as pathogen-associated molecular patterns (PAMP) [7,8,9], they mature [10] with concomitantly increased expression of costimulatory molecules, cytokines [11,12] and up-regulation of the major histocompatibility complex (MHC class I and II), all of which are immune-stimulators. During the late phase of DC maturation, DCs switch to a suppressive phenotype, which is characterized by the expression of molecules such as indoleamine 2,3-dioxygenase (IDO) [13,14,15], the soluble

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