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 selfantigens. 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.The small GTPase Ras is a potent signaling molecule that can bind with numerous downstream effector molecules including the protein kinase Raf (1, 2). Raf in turn activates the mitogenactivated protein kinase (MAPK) 2 kinase (MEK)/extracellular signal-regulated kinase (Erk) cascade (3, 4). This signaling pathway controls many pivotal functions in T cells. The ERK kinases overcome SHP-1 phosphatase blockade of proximal T cell receptor (TCR) signaling (5), and more globally, influence the maturation of T cells in the thymus (6 -9) and production of interleukin-2 (IL-2) in the post-thymic peripheral T cells (10 -14). The observation that a relative lack of Ras/ERK signal is associated with inability of T cells to respond to an antigen further underscores the fundamental role of this signaling pathway in T cell stimulation (15-17). It is not surprising to find therefore that T cells and other cell types have developed inhibitors to control the magnitude and duration of the ERK signaling. Among the most prominent endogenous repressors of the Ras/ERK signaling are GTPase-activating proteins (18, 19), downstream of tyrosine kinase (Dok) adaptor proteins (20 -22), members of the Sprouty protein family (23, 24), diacylglycerol kinases (DGK-and DGK-␣) (25, 26), ERK-specific dual specificity phosphatases (27), and a molecule with an E3 ubiquitin ligase activity described recently as impedes mitogenic signal propagation (Imp) (28).Imp, also known as BRCA1-associated protein (BRAP2), was originally identified as a...