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Sphingosine 1-Phosphate Regulates the Egress of IgA Plasmablasts from Peyer’s Patches for Intestinal IgA Responses¹

Masashi Gohda^2,*,, Jun Kunisawa^2,*,,, Fumi Miura^*, Yuki Kagiyama^*, Yosuke Kurashima^*,, Morio Higuchi^*,, Izumi Ishikawa^*,, Ikuko Ogahara^*, and Hiroshi Kiyono^3,*,,,

^* Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, Department of Medical Genome Science, Graduate School of Frontier Science, and Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology, Saitama, Japan

It is well established that Peyer’s patches (PPs) are sites for the differentiation of IgA plasma cell precursors, but molecular and cellular mechanisms in their trafficking remain to be elucidated. In this study, we show that alterations in type 1 sphingosine 1-phosphate (S1P) receptor expression during B cell differentiation in the PPs control the emigration of IgA plasma cell precursors. Type 1 S1P receptor expression decreased during the differentiation of IgM⁺B220⁺ B cells to IgA⁺B220⁺ B cells, but recovered on IgA⁺B220^– plasmablasts for their emigration from the PPs. Thus, IgA⁺B220^– plasmablasts migrated in response to S1P in vitro. Additionally, IgA⁺ plasmablasts selectively accumulated in lymphatic regions of PPs when S1P-mediated signaling was disrupted by FTY720 treatment. This accumulation of IgA⁺ plasmablasts in the PPs led to their reduction in the intestinal lamina propria and simultaneous impairment of Ag-specific intestinal IgA production against orally administered Ag. These findings suggest that S1P regulates the retention and emigration of PP B cells and plays key roles in the induction of intestinal IgA production.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Core Research for Evolutional Science and Technology of Japan Science and Technology; Ministry of Education, Science, Sports, and Culture; Ministry of Health and Welfare in Japan; Waksman Foundation; Yakult Bio-Science Foundation; and Mochida Memorial Foundation for Medical and Pharmaceutical Research.

² M.G. and J.K. contributed equally to this work and therefore share the first authorship.

³ Address correspondence and reprint requests to Dr. Hiroshi Kiyono, Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. E-mail address: kiyono{at}ims.u-tokyo.ac.jp

⁴ Abbreviations used in this paper: S-IgA, secretory IgA; AFC, Ab-forming cell; CMIS, common mucosal immune system; CSR, class switch recombination; DC, dendritic cell; GC, germinal center; iLP, intestinal lamina propria; int, intermediate; KLF2, Kruppel-like factor 2; PC, plasma cell; PNA, peanut agglutinin; PP, Peyer’s patch; S1P, sphingosine 1-phosphate; S1P₁, type 1 S1P receptor; FAE, follicle-associated epithelium.