title: Control of CD8 T cell proliferation and terminal differentiation by active STAT5 and CDKN2A/CDKN2B.
abstract: CD8 T cells used in adoptive immunotherapy may be manipulated to optimize their effector functions, tissue-migratory properties and long-term replicative potential. We reported that antigen-stimulated CD8 T cells transduced to express an active form of the transcription factor signal transducer and activator of transcription 5 (STAT5CA) maintained these properties upon adoptive transfer. We now report on the requirements of STAT5CA-expressing CD8 T cells for cell survival and proliferation in vivo. We show that STAT5CA expression allows for greater expansion of T cells in vivo, while preserving dependency on T-cell-receptor-mediated tonic stimulation for their in vivo maintenance and return to a quiescent stage. STAT5CA expression promotes the formation of a large pool of effector memory T cells that respond upon re-exposure to antigen and present an increased sensitivity to γc receptor cytokine engagement for STAT5 phosphorylation. In addition, STAT5CA expression prolongs the survival of what would otherwise be short-lived terminally differentiated KLRG1-positive effector cells with up-regulated expression of the senescence-associated p16(INK) (4A) transcripts. However, development of a KLRG1-positive CD8 T cell population was independent of either p16(INK) (4A) or p19(ARF) expression (as shown using T cells from CDKN2A(-/-) mice) but was associated with expression of transcripts encoding p15(INK) (4B) , another protein involved in senescence induction. We conclude that T-cell-receptor- and cytokine-dependent regulation of effector T cell homeostasis, as well as mechanisms leading to senescent features of a population of CD8 T cells are maintained in STAT5CA-expressing CD8 T cells, even for cells that are genetically deficient in expression of the tumour suppressors p16(INK) (4A) and p19(ARF) .
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University UM2, Marseille, France.|INSERM, U1104, Marseille, France.|CNRS UMR 7280, 13288, Marseille, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Grange
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University UM2, Marseille, France.|INSERM, U1104, Marseille, France.|CNRS UMR 7280, 13288, Marseille, France.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Giordano
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University UM2, Marseille, France.|INSERM, U1104, Marseille, France.|CNRS UMR 7280, 13288, Marseille, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Mas
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University UM2, Marseille, France.|INSERM, U1104, Marseille, France.|CNRS UMR 7280, 13288, Marseille, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Roncagalli
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, Marseille, France.|CNRS UMR7258, Marseille, France.|Aix-Marseille University UM105, Marseille, France.|Institut Paoli-Calmettes, 13009, Marseille, France.
authors.forename: Guylène
authors.initials: G
authors.lastname: Firaguay
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, Marseille, France.|CNRS UMR7258, Marseille, France.|Aix-Marseille University UM105, Marseille, France.|Institut Paoli-Calmettes, 13009, Marseille, France.
authors.forename: Jacques A
authors.initials: JA
authors.lastname: Nunes
authors.affiliation: Institut Curie, Centre Universitaire, Orsay, France.|Bat 110; CNRS UMR 3306, Orsay, France.|INSERM U1005, Orsay, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Ghysdael
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University UM2, Marseille, France.|INSERM, U1104, Marseille, France.|CNRS UMR 7280, 13288, Marseille, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Schmitt-Verhulst
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University UM2, Marseille, France.|INSERM, U1104, Marseille, France.|CNRS UMR 7280, 13288, Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Auphan-Anezin
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000276:immunology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D037181:Lectins, C-Type; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology*
chemical_list: C417743:Cdkn2a protein, mouse; C493968:Cdkn2b protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D050799:STAT5 Transcription Factor
keywords: effector CD8 T cell; gene regulation; immunotherapy; senescence; transcription factor