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Sphingosine 1-phosphate dependence in the regulation of lymphocyte trafficking to the gut epithelium

J Exp Med 204: 2335-2348, 2007
Jun Kunisawa1,2, Yosuke Kurashima1,2, Morio Higuchi1,2, Masashi Gohda1,2, Izumi Ishikawa1,2, Ikuko Ogahara1,2, Namju Kim1,2, Miki Shimizu1,2, and Hiroshi Kiyono1,2
1: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo
2: Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST)

Intraepithelial T lymphocytes (IELs) have been considered to be involved in the immunosurveillance and the maintenance of immunological homeostasis by bridging mucosal innate and acquired immunity. Several lines of evidence have revealed that IELs are derived from conventional single-positive (SP) thymocytes as well as unconventional double-negative (DN) thymocytes. Here, we show that IELs can be divided into two groups according to their dependency on sphingosine 1-phosphate (S1P) for trafficking into the intestines. CD4 or CD8αβ naïve lymphocytes originating from SP thymocytes express high levels of type 1 S1P receptor (S1P1), and their preferential migration into the large intestine is regulated by S1P. By contrast, DN thymic IEL precursors expressing either TCRαβ or TCRγδ migrate into both the small and large intestines and S1P does not play a role in the migration pathways of these DN thymic IEL precursors. Thus, down-regulation of S1P1 expression or disruption of the S1P gradient halted conventional CD4 or CD8αβ IEL trafficking into the intestines, but did not affect the trafficking of DN thymic IEL precursors. These data suggest that a lipid-mediated system provides the immunological diversity of IELs at the frontline of mucosal tissues.