title: Akt signaling is critical for memory CD8+T-cell development and tumor immune surveillance.
abstract: Memory CD8+T cells confer long-term immunity against tumors, and anticancer vaccines therefore should maximize their generation. Multiple memory CD8+T-cell subsets with distinct functional and homing characteristics exist, but the signaling pathways that regulate their development are ill defined. Here we examined the role of the serine/threonine kinase Akt in the generation of protective immunity by CD8+T cells. Akt is known to be activated by the T-cell antigen receptor and the cytokine IL-2, but its role in T-cell immunity in vivo has not been explored. Using CD8+T cells frompdk1K465E/K465Eknockin mice, we found that decreased Akt activity inhibited the survival of T cells during the effector-to-memory cell transition and abolished their differentiation into C-X-C chemokine receptor 3 (CXCR3)loCD43loeffector-like memory cells. Consequently, antitumor immunity by CD8+T cells that display defective Akt signaling was substantially diminished during the memory phase. Reduced memory T-cell survival and altered memory cell differentiation were associated with up-regulation of the proapoptotic protein Bim and the T-box transcription factor eomesodermin, respectively. These findings suggest an important role for effector-like memory CD8+T cells in tumor immune surveillance and identify Akt as a key signaling node in the development of protective memory CD8+T-cell responses.
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: Rogel
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Willoughby
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Buchan
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Leonard
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Thirdborough
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom; aymen@soton.ac.uk.|Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Aymen
authors.initials: A
authors.lastname: Al-Shamkhani
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1 / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D007156:Immunologic Memory / Q000276:immunology*; D007157:Immunologic Surveillance / Q000235:genetics / Q000276:immunology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; C515188:Cxcr3 protein, mouse; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011948:Receptors, Antigen, T-Cell; D054367:Receptors, CXCR3; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: PKB; cancer; cytotoxic T cells; immunotherapy; vaccines