title: N-ras couples antigen receptor signaling to Eomesodermin and to functional CD8+ T cell memory but not to effector differentiation.
abstract: Signals 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.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid, E-28049 Madrid, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Iborra
authors.forename: Manuel
authors.initials: M
authors.lastname: Ramos
authors.forename: David M
authors.initials: DM
authors.lastname: Arana
authors.forename: Silvia
authors.initials: S
authors.lastname: Lázaro
authors.forename: Francisco
authors.initials: F
authors.lastname: Aguilar
authors.forename: Eugenio
authors.initials: E
authors.lastname: Santos
authors.forename: Daniel
authors.initials: D
authors.lastname: López
authors.forename: Edgar
authors.initials: E
authors.lastname: Fernández-Malavé
authors.forename: Margarita
authors.initials: M
authors.lastname: Del Val
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016283:Proto-Oncogene Proteins p21(ras) / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
chemical_list: C491198:Eomes protein, mouse; D011948:Receptors, Antigen, T-Cell; D020825:T-Box Domain Proteins; D016283:Proto-Oncogene Proteins p21(ras)