title: T-cell intrinsic and extrinsic mechanisms of p27Kip1 in the regulation of CD8 T-cell memory.
abstract: CD8 T cells exhibit dynamic alterations in proliferation and apoptosis during various phases of the CD8 T-cell response, but the mechanisms that regulate cellular proliferation from the standpoint of CD8 T-cell memory are not well defined. The cyclin-dependent kinase inhibitor p27(Kip1) functions as a negative regulator of the cell cycle in T cells, and it has been implicated in regulating cellular processes, including differentiation, transcription and migration. Here, we investigated whether p27(Kip1) regulates CD8 T-cell memory by T-cell-intrinsic or T-cell-extrinsic mechanisms, by conditional ablation of p27(Kip1) in T cells or non-T cells. Studies of T-cell responses to an acute viral infection show that p27(Kip1) negatively regulates the proliferation of CD8 T cells by T-cell-intrinsic mechanisms. However, the enhanced proliferation of CD8 T cells induced by T-cell-specific p27(Kip1) deficiency minimally affects the primary expansion or the magnitude of CD8 T-cell memory. Unexpectedly, p27(Kip1) ablation in non-T cells markedly augmented the number of high-quality memory CD8 T cells by enhancing the accumulation of memory precursor effector cells without increasing their proliferation. Further studies show that p27(Kip1) deficiency in immunizing dendritic cells fail to enhance CD8 T-cell memory. Nevertheless, we have delineated the T-cell-intrinsic, anti-proliferative activities of p27(Kip1) in CD8 T cells from its role as a factor in non-T cells that restricts the development of CD8 T-cell memory. These findings have implications in vaccine development and understanding the mechanisms that maintain T-cell homeostasis.
authors.affiliation: Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Jatzek
authors.forename: Melba
authors.initials: M
authors.lastname: Marie Tejera
authors.forename: Erin H
authors.initials: EH
authors.lastname: Plisch
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Fero
authors.forename: M
authors.initials: M
authors.lastname: Suresh
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D049109:Cell Proliferation; D002999:Clone Cells; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism; D017353:Gene Deletion; D007156:Immunologic Memory / Q000276:immunology*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000473:pathology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27