TY - JOUR
T1 - Distinct oxysterol requirements for positioning naïve and activated dendritic cells in the spleen
AU - Lu, Erick
AU - Dang, Eric V.
AU - McDonald, Jeffrey G
AU - Cyster, Jason G.
N1 - Publisher Copyright:
2017 © The Authors.
PY - 2017
Y1 - 2017
N2 - 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 7,25-hydroxycholesterol (7,25-HC). We now provide evidence that a second EBI2 ligand, 7,27-HC, is involved in splenic DCIR2+ DC positioning and homeostasis. Cyp27a1, the enzyme uniquely required for 7,27-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 7,27-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.
AB - 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 7,25-hydroxycholesterol (7,25-HC). We now provide evidence that a second EBI2 ligand, 7,27-HC, is involved in splenic DCIR2+ DC positioning and homeostasis. Cyp27a1, the enzyme uniquely required for 7,27-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 7,27-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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U2 - 10.1126/sciimmunol.aal5237
DO - 10.1126/sciimmunol.aal5237
M3 - Article
C2 - 28738017
AN - SCOPUS:85044661349
SN - 2470-9468
VL - 2
JO - Science Immunology
JF - Science Immunology
IS - 10
M1 - eaal5237
ER -