title: The CD8+ memory T-cell state of readiness is actively maintained and reversible.
abstract: The ability of the adaptive immune system to respond rapidly and robustly upon repeated antigen exposure is known as immunologic memory, and it is thought that acquisition of memory T-cell function is an irreversible differentiation event. In this study, we report that many phenotypic and functional characteristics of antigen-specific CD8 memory T cells are lost when they are deprived of contact with dendritic cells. Under these circumstances, memory T cells reverted from G(1) to the G(0) cell-cycle state and responded to stimulation like naive T cells, as assessed by proliferation, dependence upon costimulation, and interferon-gamma production, without losing cell surface markers associated with memory. The memory state was maintained by signaling via members of the tumor necrosis factor receptor superfamily, CD27 and 4-1BB. Foxo1, a transcription factor involved in T-cell quiescence, was reduced in memory cells, and stimulation of naive CD8 cells via CD27 caused Foxo1 to be phosphorylated and emigrate from the nucleus in a phosphatidylinositol-3 kinase-dependent manner. Consistent with these results, maintenance of G(1) in vivo was compromised in antigen-specific memory T cells in vesicular stomatitis virus-infected CD27-deficient mice. Therefore, sustaining the functional phenotype of T memory cells requires active signaling and maintenance.
authors.affiliation: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Atef
authors.initials: A
authors.lastname: Allam
authors.forename: Dietrich B
authors.initials: DB
authors.lastname: Conze
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Giardino Torchia
authors.forename: Ivana
authors.initials: I
authors.lastname: Munitic
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Sowell
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Marzo
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashwell
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D002467:Cell Nucleus / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000276:immunology; D016193:G1 Phase / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology; D054243:Vesicular Stomatitis / Q000276:immunology; D018116:Vesiculovirus / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases