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T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow.

  • Author(s): Jenne, Craig N;
  • Enders, Anselm;
  • Rivera, Richard;
  • Watson, Susan R;
  • Bankovich, Alexander J;
  • Pereira, Joao P;
  • Xu, Ying;
  • Roots, Carla M;
  • Beilke, Joshua N;
  • Banerjee, Arnob;
  • Reiner, Steven L;
  • Miller, Sara A;
  • Weinmann, Amy S;
  • Goodnow, Chris C;
  • Lanier, Lewis L;
  • Cyster, Jason G;
  • Chun, Jerold
  • et al.
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.

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