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¹ Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
² Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi, Saitama 322-0012, Japan

CORRESPONDENCE Hiroshi Kiyono:kiyono{at}ims.u-tokyo.ac.jp

It is well established that intraepithelial T lymphocytes (IELs) are derived from conventional single-positive (SP) thymocytes, as well as unconventional double-negative (DN) thymocytes and CD103⁺CD8ß recent thymic emigrants (RTEs). 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 CD8ß naive 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. In contrast, RTEs migrate exclusively into the small intestine, whereas DN thymic IEL precursors expressing either TCRß or TCR migrate into both the small and large intestines. S1P does not play a role in the migration pathways of these unconventional thymic IEL precursors. Thus, down-regulation of S1P₁ expression or disruption of the S1P gradient halted conventional CD4 or CD8ß IEL trafficking into the intestines, but did not affect the trafficking of unconventional thymic IEL precursors. These data are the first to demonstrate that a lipid-mediated system discriminates IELs originating from conventional and unconventional thymic precursors.

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