Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 206, Issue 11, Pages 2469-2481Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20090525
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Funding
- Deutsche Forschungsgemeinschaft Research Fellowship [EN 790/1-1]
- National Institute of Allergy and Infectious Disease [AI061061]
- National Institute of General Medical Sciences [T3207270]
- Ramaciotti Foundation
- National Institutes of Health [AI52127, BAA-NIH-NIAID-DAIT-07-35, AI74847, DA019674]
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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 (S1P(5)) transcript levels, and S1P(5)-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 S1P(1) 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 S1P(5) as a T-bet-induced gene that is required for NK cell egress from LNs and BM.
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