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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4646-4652.
Prepublished online as a Blood First Edition Paper on February 21, 2008; DOI 10.1182/blood-2007-10-120071.
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IMMUNOBIOLOGY
Sphingosine 1-phosphate–dependent trafficking of peritoneal B cells requires functional NF B-inducing kinase in stromal cells
Jun Kunisawa*,13,
Masashi Gohda*,1,2,
Yosuke Kurashima1,4,
Izumi Ishikawa1,3,
Morio Higuchi1,4, and
Hiroshi Kiyono14
1 Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, University of Tokyo, Tokyo;
2 Department of Medical Genome Science, Graduate School of Frontier Science, University of Tokyo, Tokyo;
3 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Saitama; and
4 Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan
We previously reported that sphingosine 1-phosphate (S1P) regulates peritoneal B-cell trafficking and subsequent intestinal IgA production, but the underlying mechanisms remain obscure. We demonstrate here that nuclear factor  B–inducing kinase (NIK) is involved in the regulation of S1P-mediated trafficking of peritoneal B cells. Although peritoneal B cells from NIK-mutated alymphoplasia (aly) mice expressed type 1 S1P receptor (S1P1) at comparable levels and demonstrated normal migration toward S1P, aly peritoneal B cells showed decreased sensitivity to FTY720, an S1P1 modulator. NIK-mutated stromal cells showed decreased levels of adhesion molecules (VCAM-1 and ICAM-1) and increased CXCL13 expressions, leading to impaired ability to support S1P-mediated emigration, but not immigration, of peritoneal B cells. Therefore, aly peritoneal B cells exhibited normal S1P-mediated peritoneal B-cell trafficking from peritoneum to intestine for IgA production when they were transferred into severe combined immunodeficient or wild-type mice. However, S1P-mediated emigration of wild-type B cells from the aly peritoneal cavity was impaired without affecting their immigration from the blood. Further, transfer of wild-type stromal cells into the peritoneum restored S1P-mediated trafficking of aly peritoneal B cells. These findings suggest that NIK in stromal cells has a specific role in the regulation of S1P-mediated trafficking of peritoneal B cells.
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