title: T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Jenne
authors.forename: Anselm
authors.initials: A
authors.lastname: Enders
authors.forename: Richard
authors.initials: R
authors.lastname: Rivera
authors.forename: Susan R
authors.initials: SR
authors.lastname: Watson
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Bankovich
authors.forename: Joao P
authors.initials: JP
authors.lastname: Pereira
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Carla M
authors.initials: CM
authors.lastname: Roots
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Beilke
authors.forename: Arnob
authors.initials: A
authors.lastname: Banerjee
authors.forename: Steven L
authors.initials: SL
authors.lastname: Reiner
authors.forename: Sara A
authors.initials: SA
authors.lastname: Miller
authors.forename: Amy S
authors.initials: AS
authors.lastname: Weinmann
authors.forename: Chris C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
mesh_terms: 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
chemical_list: 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