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J. Biol. Chem., Vol. 283, Issue 34, 23004-23015, August 22, 2008

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p21 Ras/Impedes Mitogenic Signal Propagation Regulates Cytokine Production and Migration in CD4 T Cells^*

Jan Czyzyk¹, Hui-Chen Chen, Kim Bottomly, and Richard A. Flavell^¶

From the Departments of Pathology and Immunobiology and the ^¶Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520

The propensity of T cells to generate coordinated cytokine responses is critical for the host to develop resistance to pathogens while maintaining the state of immunotolerance to self-antigens. The exact mechanisms responsible for preventing the overproduction of proinflammatory cytokines including interferon (IFN)- are not fully understood, however. In this study, we examined the role of a recently described Ras GTPase effector and repressor of the Raf/MEK/ERK cascade called impedes mitogenic signal propagation (Imp) in limiting the induction of T-cell cytokines. We found that stimulation of the T cell receptor complex leads to the rapid development of a physical association between Ras and Imp. Consistent with the hypothesis that Imp inhibits signal transduction, we also found that disengagement of this molecule by the Ras^V12G37 effector loop mutant or RNA interference markedly enhances the activation of the NFAT transcription factor and IFN- secretion. A strong output of IFN- is responsible for the distinct lymphocyte traffic pattern observed in vivo because the transgenic or retroviral expression of Ras^V12G37 caused T cells to accumulate preferentially in the lymph nodes and delayed their escape from the lymphoid tissue, respectively. Together, our results describe a hitherto unrecognized negative regulatory role for Imp in the production of IFN- in T cells and point to Ras-Imp binding as an attractive target for therapeutic interventions in conditions involving the production of this inflammatory cytokine.

Received for publication, May 28, 2008 , and in revised form, June 23, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01 5R37A1026791-18 (to K. B.). This work was also supported by an American Cancer Society Research Scholar Grant (to J. C.). 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: 300 Cedar St., TAC S546, New Haven, CT 06519. Fax: 203-737-1765; E-mail: jan.czyzyk{at}yale.edu.

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