Research ArticleDENDRITIC CELLS

Distinct oxysterol requirements for positioning naïve and activated dendritic cells in the spleen

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Science Immunology  07 Apr 2017:
Vol. 2, Issue 10, eaal5237
DOI: 10.1126/sciimmunol.aal5237

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Programming dendritic cells with cholesterol

Strategic positioning of immune cells at sites of pathogen encounter plays a critical role in mounting effective immune responses. Epstein-Barr virus–induced gene 2 (EBI2) is a G protein–coupled receptor activated by 7α,25-hydroxycholesterol (7α,25-HC) and plays an essential function in positioning naïve dendritic cells (DCs) during antigen encounter in the mouse spleen. By studying mouse strains that lack key enzymes involved in the synthesis of 7α,25-HC and related sterols, Lu et al. have found 7α,27-HC as a second physiological ligand for EBI2. Further, they show that the role of EBI2 is multitiered, as it is also employed by activated DCs to colocalize with activated helper T cells in the outer T cell zone. They also reveal factors that help shape EBI2 ligand gradients. Their studies add to our growing appreciation of how metabolites influence immune responses.

Abstract

Correct positioning of dendritic cells (DCs) is critical for efficient pathogen encounter and antigen presentation. Epstein-Barr virus–induced gene 2 (EBI2) has been identified as a chemoattractant receptor required for naïve CD4+DCIR2+ DC positioning in response to 7α,25-hydroxycholesterol (7α,25-HC). We now provide evidence that a second EBI2 ligand, 7α,27-HC, is involved in splenic DCIR2+ DC positioning and homeostasis. Cyp27a1, the enzyme uniquely required for 7α,27-HC synthesis, is expressed by stromal cells in the region of naïve DC localization. After activation, DCIR2+ DCs move into the T cell zone. We find that EBI2 is rapidly up-regulated in DCIR2+ DCs under certain activation conditions, and positioning at the B-T zone interface depends on EBI2. Under conditions of type I interferon induction, EBI2 ligand levels are elevated, causing activated DCIR2+ DCs to disperse throughout the T zone. Last, we provide evidence that oxysterol metabolism by Batf3-dependent DCs is important for EBI2-dependent positioning of activated DCIR2+ DCs. This work indicates that 7α,27-HC functions as a guidance cue in vivo and reveals a multitiered role for EBI2 in DC positioning. Deficiency in this organizing system results in defective CD4+ T cell responses.

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