p21 Ras/impedes mitogenic signal propagation regulates cytokine production and migration in CD4 T cells

Jan Czyzyk, Hui Chen Chen, Kim Bottomly, Richard A. Flavell

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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)-γ 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-γ secretion. A strong output of IFN-γ is responsible for the distinct lymphocyte traffic pattern observed in vivo because the transgenic or retroviral expression of RasV12G37 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-γ 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.

Original languageEnglish (US)
Pages (from-to)23004-23015
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number34
DOIs
StatePublished - Aug 22 2008
Externally publishedYes

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