title: Prosurvival Bcl-2 family members reveal a distinct apoptotic identity between conventional and plasmacytoid dendritic cells.
abstract: Dendritic cells (DCs) are heterogeneous, comprising subsets with functional specializations that play distinct roles in immunity as well as immunopathology. We investigated the molecular control of cell survival of two main DC subsets: plasmacytoid DCs (pDCs) and conventional DCs (cDCs) and their dependence on individual antiapoptotic BCL-2 family members. Compared with cDCs, pDCs had higher expression of BCL-2, lower A1, and similar levels of MCL-1 and BCL-XL. Transgenic overexpression of BCL-2 increased the pDC pool size in vivo with only minor impact on cDCs. With a view to immune intervention, we tested BCL-2 inhibitors and found that ABT-199 (the BCL-2 specific inhibitor) selectively killed pDCs but not cDCs. Conversely, genetic knockdown of A1 profoundly reduced the proportion of cDCs but not pDCs. We also found that conditional ablation of MCL-1 significantly reduced the size of both DC populations in mice and impeded DC-mediated immune responses. Thus, we revealed that the two DC types have different cell survival requirements. The molecular basis of survival of different DC subsets thus advocates the antagonism of selective BCL-2 family members for treating diseases pertaining to distinct DC subsets.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Carrington
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Sutherland
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: Ingela B
authors.initials: IB
authors.lastname: Vikstrom
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Brady
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
authors.forename: Priscilla
authors.initials: P
authors.lastname: Soo
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
authors.forename: David
authors.initials: D
authors.lastname: Vremec
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: Cody
authors.initials: C
authors.lastname: Allison
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: Erinna F
authors.initials: EF
authors.lastname: Lee
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Fairlie
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grabow
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and Department of Immunology, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Ottina
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Herold
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: David M
authors.initials: DM
authors.lastname: Tarlinton
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and Department of Microbiology and Immunology, University of Melbourne, Parkville, VIC 3010, Australia; and lew@wehi.edu.au zhan@wehi.edu.au.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and lew@wehi.edu.au zhan@wehi.edu.au.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhan
mesh_terms: D000818:Animals; D017209:Apoptosis; D002469:Cell Separation; D002470:Cell Survival; D003713:Dendritic Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D019076:Transgenes; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494812:Bcl2l1 protein, mouse; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C052617:Bcl2 protein, mouse
keywords: BH3-mimetic; apoptosis; dendritic cells