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Cutting Edge: Modulation of Intestinal Autoimmunity and IL-2 Signaling by Sphingosine Kinase 2 Independent of Sphingosine 1-Phosphate¹

Eileen T. Samy^*, Claas A. Meyer, Patrick Caplazi^*, Claire L. Langrish^*, Jose M. Lora^*, Horst Bluethmann and Stanford L. Peng^2,*

^* Inflammation, Autoimmunity, and Transplantation Research, Roche Palo Alto, Palo Alto, CA 94304; and F. Hoffmann-La Roche, Roche Center for Medical Genomics, Basel, Switzerland

Sphingosine kinase (Sphk) phosphorylates sphingosine into sphingosine-1-phosphate (S1P), but its recently identified isoform Sphk2 has been suggested to have distinct subcellular localization and substrate specificity. We demonstrate here that, surprisingly, Sphk2^–/– CD4⁺ T cells exhibit a hyperactivated phenotype with significantly enhanced proliferation and cytokine secretion in response to IL-2 as well as reduced sensitivity to regulatory T cell-mediated suppression in vitro, apparently independent of effects upon S1P. Such findings appear to reflect a requirement for Sphk2 to suppress IL-2 signaling because, in Sphk2^–/– CD4⁺ T cells, IL-2 induced abnormally accentuated STAT5 phosphorylation and small interfering RNA knockdown of STAT5 abrogated their hyperactive phenotype. This pathway physiologically modulates autoinflammatory responses, because Sphk2^–/– T cells induced more rapid and robust inflammatory bowel disease in scid recipients. Thus, Sphk2 regulates IL-2 pathways in T cells, and the modulation of Sphk2 activity may be of therapeutic utility in inflammatory and/or infectious diseases.

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 in part by National Institutes of Health Grant R01 AI057571.

² Address correspondence and reprint requests to Dr. Stanford L. Peng, Mail Stop R7-101, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304. E-mail address: stanford.peng{at}roche.com

³ Abbreviations used in this paper: Sphk, sphingosine kinase; IBD, inflammatory bowel disease; pSTAT5, phosphorylated STAT5; siRNA, small interfering RNA; S1P, sphingosine-1-phosphate; Treg, regulatory T cell.