The Role of Sphingosine-1-Phosphate Transporter Spns2 in Immune System Function
Authors: Nijnik Anastasia , Clare Simon , Hale Christine , Chen Jing , Raisen Claire , Mottram Lynda , Lucas Mark , Estabel Jeanne , Ryder Edward , Adissu Hibret ,   Sanger Mouse Genetics Project, Bradley Allan , Ramirez-Solis Ramiro , Adams David J. , White Jacqueline K. , Adams Niels C. , Steel Karen , Skarnes Bill , Dougan Gordon , Melvin David , Gannon David , Griffiths Mark , Kipp Christian , Evans Arthur , Holroyd Simon , Barnes Caroline , Cambridge Emma , Carragher Damian , Clare Simon , Clarke Kay , Protheroe Hayley , Estabel Jeanne , Gerdin Anna-Karin , Hooks Yvette , Igosheva Natalia , Ismail Ozama , Kane Leanne , Karp Natasha , Lafont David Tino , Lucas Mark , Maguire Simon , McGill Katherine , Mottram Lynda , Mulderrig Lee , Podrini Christine , Protheroe Hayley , Roberson Laura , Salsbury Grace , Sanger Daniel , Sanderson Mark , Shannon Carl , Sunter David , Tuck Elizabeth , Vancollie Valerie , Bhattacharjee Debarati , Cook Ross , Gleeson Diane , Hardy Matt hew , Haskins Claire , Jhaveri Kalpesh , Price Stacey , Ryder Edward , Sethi Debarati , Vyas Sapna , Bottomley Joanna , Brown Ellen , Bussell James , Grau Evelyn , Houghton Richard , Kundi Helen , Madich Alla , Mayhew Danielle , Metcalf Tom , Newman Stuart , Pearson Laila , Sinclair Caroline , Wardle-Jones Hannah , Woods Mike , Adams Niels C. , Ramirez-Solis Ramiro , White Jacqueline K. , Steel Karen P. , Dougan Gordon , Hancock Robert E. W. 
Published: June 2012

Sphingosine-1-phosphate (S1P) is lipid messenger involved in the regulation of embryonic development, immune system functions, and many other physiological processes. However, the mechanisms of S1P transport across cellular membranes remain poorly understood, with several ATP-binding cassette family members and the spinster 2 (Spns2) member of the major facilitator superfamily known to mediate S1P transport in cell culture. Spns2 was also shown to control S1P activities in zebrafish in vivo and to play a critical role in zebrafish cardiovascular development. However, the in vivo roles of Spns2 in mammals and its involvement in the different S1P-dependent physiological processes have not been investigated. In this study, we characterized Spns2-null mouse line carrying the Spns2tm1a(KOMP)Wtsi allele (Spns2tm1a). The Spns2tm1a/tm1a animals were viable, indicating a divergence in Spns2 function from its zebrafish ortholog. However, the immunological phenotype of the Spns2tm1a/tm1a mice closely mimicked the phenotypes of partial S1P deficiency and impaired S1P-dependent lymphocyte trafficking, with a depletion of lymphocytes in circulation, an increase in mature single-positive T cells in the thymus, and a selective reduction in mature B cells in the spleen and bone marrow. Spns2 activity in the nonhematopoietic cells was critical for normal lymphocyte development and localization. Overall, Spns2tm1a/tm1a resulted in impaired humoral immune responses to immunization. This study thus demonstrated a physiological role for Spns2 in mammalian immune system functions but not in cardiovascular development. Other components of the S1P signaling network are investigated as drug targets for immunosuppressive therapy, but the selective action of Spns2 may present an advantage in this regard.