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J. Biol. Chem., Vol. 282, Issue 3, 1964-1972, January 19, 2007

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Distinctive T Cell-suppressive Signals from Nuclearized Type 1 Sphingosine 1-Phosphate G Protein-coupled Receptors^*

Jia-Jun Liao, Mei-Chuan Huang, Markus Graler^¶, Yong Huang^||, Hong Qiu, and Edward J. Goetzl¹

From the Departments of Medicine, Microbiology-Immunology, and ^||Biopharmaceutical Sciences, University of California, San Francisco, California 94143 and ^¶Institute for Immunology, Medical School Hannover, 30625 Hannover, Germany

Sphingosine 1-phosphate (S1P) generated by cells of innate immunity and the type 1 S1P G protein-coupled receptor (S1P₁) on mobile T cells constitute a major system for control of lymphoid organ traffic and tissue migration of T cells. Now we show that T cell activation mediated by the T cell antigen receptor translocates plasma membrane S1P₁ to nuclear envelope membranes for association there with G_i/o, Erk , and other proteins that plasma membrane S1P₁ uses to signal T cell proliferation. However, nuclear S1P₁ and plasma membrane S1P₁ transduce opposite effects of S1P on T cell proliferation and relevant signaling as exemplified by respective decreases and increases in T cell nuclear concentrations of both phospho-Erk and active (phosphorylated) c-Jun. T cell antigen receptor-mediated activation of T cells therefore both eliminates migration responses to S1P by down-regulation of plasma membrane S1P₁ and translocates the S1P-S1P₁ axis into the nuclear domain where signals are directed to transcriptional control of immune functions other than migration.

Received for publication, September 6, 2006 , and in revised form, October 31, 2006.

^* This work was supported in large part by National Institutes of Health Grants RO-1 HL31809 and PO-1 HL68738. 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 To whom correspondence should be addressed: University of California, Rm. UB8B, UC Box 0711, 533 Parnassus at 4th Ave., San Francisco, CA 94143. Tel.: 415-476-5339; Fax: 415-476-6915; E-mail: edward.goetzl{at}ucsf.edu.

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