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 - Funding Information:
We thank J. An and Y. Xu for expert technical assistance, B. M. Thompson and K. M. Eckert for technical assistance with LC-MS/MS, D. Russell for enzyme-deficient mice and Cyp27a1 antisera, T. Yi and J. Muppidi for helpful discussions, and L. Rodda and J. Wu for critical reading of the manuscript. E.L. was supported by the University of California San Francisco (UCSF) Biomedical Sciences Graduate Program and NSF grant 1144247. E.V.D. was supported by the UCSF Medical Scientist Training Program and NIH F30 grant F30AI120527. J.G.C. is an investigator of the Howard Hughes Medical Institute. This work was supported in part by NIH grant AI040098, and the mass spectrometry work was supported by grant HL20948.
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 -