T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow.
During a screen for ethylnitrosourea-induced mutations in mice affecting blood natural killer (NK) cells, we identified a strain, designated Duane, in which NK cells were reduced in blood and spleen but increased in lymph nodes (LNs) and bone marrow (BM). The accumulation of NK cells in LNs reflected a decreased ability to exit into lymph. This strain carries a point mutation within Tbx21 (T-bet), which generates a defective protein. Duane NK cells have a 30-fold deficiency in sphingosine-1-phosphate receptor 5 (S1P5) transcript levels, and S1P5-deficient mice exhibit an egress defect similar to Duane. Chromatin immunoprecipitation confirms binding of T-bet to the S1pr5 locus. S1P-deficient mice exhibit a more severe NK cell egress block, and the FTY720-sensitive S1P1 also plays a role in NK cell egress from LNs. S1P5 is not inhibited by CD69, a property that may facilitate trafficking of activated NK cells to effector sites. Finally, the accumulation of NK cells within BM of S1P-deficient mice was associated with reduced numbers in BM sinusoids, suggesting a role for S1P in BM egress. In summary, these findings identify S1P5 as a T-bet-induced gene that is required for NK cell egress from LNs and BM.
Jenne
Craig N
CN
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Enders
Anselm
A
Rivera
Richard
R
Watson
Susan R
SR
Bankovich
Alexander J
AJ
Pereira
Joao P
JP
Xu
Ying
Y
Roots
Carla M
CM
Beilke
Joshua N
JN
Banerjee
Arnob
A
Reiner
Steven L
SL
Miller
Sara A
SA
Weinmann
Amy S
AS
Goodnow
Chris C
CC
Lanier
Lewis L
LL
Cyster
Jason G
JG
Chun
Jerold
J
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D005038:Ethylnitrosourea; D000068876:Fingolimod Hydrochloride; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology* / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D008246:Lysophospholipids / Q000172:deficiency / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D011409:Propylene Glycols / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000172:deficiency / Q000494:pharmacology; D020825:T-Box Domain Proteins / Q000378:metabolism*; D000098815:T-bet Transcription Factor
D008246:Lysophospholipids; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D005038:Ethylnitrosourea