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Oxysterol requirements for positioning naïve and activated dendritic cells

  • Author(s): Lu, Erick
  • Advisor(s): Cyster, Jason G
  • et al.
Abstract

Correct positioning of dendritic cells (DCs) is critical for efficient pathogen encounter and antigen presentation. Epstein-Barr virus–induced gene 2 (EBI2) is a chemoattractant receptor required for naïve CD4+DCIR2+ DC positioning in response to 7α,25-hydroxycholesterol (7α,25-HC). However, mice lacking Ch25h, an enzyme required for generating 7α,25-HC, exhibit an incomplete splenic DCIR2+ DC defect compared to mice lacking EBI2. We provide evidence that a second EBI2 ligand, 7α,27-HC, can function as a guidance cue to support splenic DCIR2+ DC positioning and homeostasis. Cyp27a1, an enzyme required for 7α,27-HC synthesis, is expressed by stromal cells in the region of naïve DC localization. Mice lacking both Cyp27a1 and Ch25h have a similar deficiency in DCIR2+ DCs compared to mice lacking EBI2. After activation, DCIR2+ DCs migrate to the T cell zone. In some contexts, they position at the B-T zone interface, where they interact with activated CD4+ T cells. The guidance cues that support positioning of activated DCIR2+ DCs at this interface are undefined. We find that EBI2 is upregulated in DCIR2+ DCs in response to certain stimuli, and positioning at the B-T zone interface requires EBI2 and Ch25h. Under conditions of type I IFN induction, EBI2 ligand levels are elevated, causing activated DCIR2+ DCs to disperse throughout the T zone. Last, we provide evidence that oxysterol metabolism by XCR1+ DCs is important for EBI2-dependent positioning of activated DCIR2+ DCs. This work reveals a multi-tiered role for EBI2 in DC positioning. Deficiency in this organizing system results in defective CD4+ T cell responses.

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