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N-ras couples antigen receptor signaling to eomesodermin and to functional cd8+ t cell memory but not to effector differentiation

AutorIborra, Salvador; Ramos, Manuel ; Arana, David M.; Lázaro, Silvia ; Aguilar, Francisco; Santos de Dios, Eugenio ; López, Daniel ; Fernández-Malavé, Edgar ; Val, Margarita del
Palabras claveMature DC
Mammalian target of rapamycin
Post infection
Vaccinia virus
Phosphoinositide 3-kinase
Eomesodermin
Extracellular signal-regulated kinase
Fecha de publicación2013
EditorRockefeller University Press
CitaciónJournal of Experimental Medicine 210(7): 1463-1479 (2013)
ResumenSignals from the TCR that specifically contribute to effector versus memory CD8+ T cell differentiation are poorly understood. Using mice and adoptively transferred T lymphocytes lacking the small GTPase N-ras, we found that N-ras-deficient CD8+ T cells differentiate efficiently into antiviral primary effectors but have a severe defect in generating protective memory cells. This defect was rescued, although only partly, by rapamycin-mediated inhibition of mammalian target of rapamycin (mTOR) in vivo. The memory defect correlated with a marked impairment in vitro and in vivo of the antigen-mediated early induction of T-box transcription factor Eomesodermin (Eomes), whereas T-bet was unaffected. Besides N-ras, early Eomes induction in vitro required phosphoinositide 3-kinase (PI3K)-AKT but not extracellular signal-regulated kinase (ERK) activation, and it was largely insensitive to rapamycin. Consistent with N-ras coupling Eomes to T cell memory, retrovirally enforced expression of Eomes in N-ras-deficient CD8+ T cells effectively rescued their memory differentiation. Thus, our study identifies a critical role for N-ras as a TCR-proximal regulator of Eomes for early determination of the CD8+ T cell memory fate. © 2013 Iborra et al.
DescripciónThis article is distributed under the terms of an Attribution– Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date. After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license.
Versión del editorhttp://dx.doi.org/10.1084/jem.20112495
URIhttp://hdl.handle.net/10261/98181
DOI10.1084/jem.20112495
Identificadoresissn: 0022-1007
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