title: Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins.
abstract: During the effector CD8+ T-cell response, transcriptional differentiation programs are engaged that promote effector T cells with varying memory potential. Although these differentiation programs have been used to explain which cells die as effectors and which cells survive and become memory cells, it is unclear if the lack of cell death enhances memory. Here, we investigated effector CD8+ T-cell fate in mice whose death program has been largely disabled because of the loss of Bim. Interestingly, the absence of Bim resulted in a significant enhancement of effector CD8+ T cells with more memory potential. Bim-driven control of memory T-cell development required T-cell-specific, but not dendritic cell-specific, expression of Bim. Both total and T-cell-specific loss of Bim promoted skewing toward memory precursors, by enhancing the survival of memory precursors, and limiting the availability of IL-15. Decreased IL-15 availability in Bim-deficient mice facilitated the elimination of cells with less memory potential via the additional pro-apoptotic molecules Noxa and Puma. Combined, these data show that Bim controls memory development by limiting the survival of pre-memory effector cells. Further, by preventing the consumption of IL-15, Bim limits the role of Noxa and Puma in causing the death of effector cells with less memory potential.
authors.affiliation: Department of Pediatrics, Division of Immunobiology at the Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kurtulus
authors.affiliation: Department of Pediatrics, Division of Immunobiology at the Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sholl
authors.affiliation: Infection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Toe
authors.affiliation: Department of Pediatrics, Division of Immunobiology at the Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: P
authors.initials: P
authors.lastname: Tripathi
authors.affiliation: Department of Pediatrics, Division of Immunobiology at the Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: J
authors.initials: J
authors.lastname: Raynor
authors.affiliation: Department of Pediatrics, Division of Immunobiology at the Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: K-P
authors.initials: KP
authors.lastname: Li
authors.affiliation: Infection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Department of Pediatrics, Division of Immunobiology at the Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Hildeman
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology*; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D007156:Immunologic Memory / Q000502:physiology*; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D019409:Interleukin-15; D008565:Membrane Proteins; C488588:PUMA protein, mouse; C408009:Pmaip1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins