Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress.
T cell egress from the thymus is essential for adaptive immunity and involves chemotaxis along a sphingosine-1-phosphate (S1P) gradient. Pericytes at the corticomedullary junction produce the S1P egress signal, whereas thymic parenchymal S1P levels are kept low through S1P lyase (SPL)-mediated metabolism. Although SPL is robustly expressed in thymic epithelial cells (TECs), in this study, we show that deleting SPL in CD11c+dendritic cells (DCs), rather than TECs or other stromal cells, disrupts the S1P gradient, preventing egress. Adoptive transfer of peripheral wild-type DCs rescued the egress phenotype of DC-specific SPL knockout mice. These studies identify DCs as metabolic gatekeepers of thymic egress. Combined with their role as mediators of central tolerance, DCs are thus poised to provide homeostatic regulation of thymic export.
Center for Cancer Research, University of California, San Francisco Benioff Children's Hospital, Oakland, CA 94609.
Jesus
J
Zamora-Pineda
Center for Cancer Research, University of California, San Francisco Benioff Children's Hospital, Oakland, CA 94609.
Ashok
A
Kumar
Center for Cancer Research, University of California, San Francisco Benioff Children's Hospital, Oakland, CA 94609.
Jung H
JH
Suh
Center for Cancer Research, University of California, San Francisco Benioff Children's Hospital, Oakland, CA 94609.
Meng
M
Zhang
Center for Cancer Research, University of California, San Francisco Benioff Children's Hospital, Oakland, CA 94609 jsaba@chori.org.
Julie D
JD
Saba
D019264:Adoptive Transfer; D000446:Aldehyde-Lyases / Q000378:metabolism*; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology*; D042783:Endothelial Cells / Q000201:enzymology; D004847:Epithelial Cells / Q000201:enzymology; D005110:Extracellular Space / Q000378:metabolism; D006410:Hematopoiesis; D008246:Lysophospholipids / Q000097:blood; D008264:Macrophages / Q000166:cytology; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D010641:Phenotype; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000097:blood; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*
D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D013110:Sphingosine