PMID- 25775525 OWN - NLM STAT- MEDLINE DCOM- 20150622 LR - 20220408 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 112 IP - 13 DP - 2015 Mar 31 TI - Prosurvival Bcl-2 family members reveal a distinct apoptotic identity between conventional and plasmacytoid dendritic cells. PG - 4044-9 LID - 10.1073/pnas.1417620112 [doi] AB - 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. FAU - Carrington, Emma M AU - Carrington EM AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Zhang, Jian-Guo AU - Zhang JG AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Sutherland, Robyn M AU - Sutherland RM AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Vikstrom, Ingela B AU - Vikstrom IB AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Brady, Jamie L AU - Brady JL AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Soo, Priscilla AU - Soo P AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; FAU - Vremec, David AU - Vremec D AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; FAU - Allison, Cody AU - Allison C AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Lee, Erinna F AU - Lee EF AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Fairlie, W Douglas AU - Fairlie WD AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Bouillet, Philippe AU - Bouillet P AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Grabow, Stephanie AU - Grabow S AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Ottina, Eleonora AU - Ottina E AD - 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. FAU - Herold, Marco J AU - Herold MJ AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Pellegrini, Marc AU - Pellegrini M AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Huang, David C S AU - Huang DC AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Tarlinton, David M AU - Tarlinton DM AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Strasser, Andreas AU - Strasser A AD - Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, and. FAU - Lew, Andrew M AU - Lew AM AD - 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. FAU - Zhan, Yifan AU - Zhan Y AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150316 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Bcl2l1 protein, mouse) RN - 0 (Mcl1 protein, mouse) RN - 0 (Myeloid Cell Leukemia Sequence 1 Protein) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (bcl-X Protein) RN - 114100-40-2 (Bcl2 protein, mouse) SB - IM MH - Animals MH - *Apoptosis MH - Cell Separation MH - Cell Survival MH - Dendritic Cells/*cytology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Myeloid Cell Leukemia Sequence 1 Protein/metabolism MH - Proto-Oncogene Proteins c-bcl-2/*metabolism MH - Signal Transduction MH - Spleen/immunology/metabolism MH - T-Lymphocytes/cytology MH - Transgenes MH - bcl-X Protein/metabolism PMC - PMC4386329 OTO - NOTNLM OT - BH3-mimetic OT - apoptosis OT - dendritic cells COIS- Conflict of interest statement: All authors are employees of the Walter and Eliza Hall Institute of Medical Research. This institute receives milestone payments for the development of BH3 mimetic drugs for therapy from Genentech and AbbVie. EDAT- 2015/03/17 06:00 MHDA- 2015/06/24 06:00 PMCR- 2015/09/30 CRDT- 2015/03/17 06:00 PHST- 2015/03/17 06:00 [entrez] PHST- 2015/03/17 06:00 [pubmed] PHST- 2015/06/24 06:00 [medline] PHST- 2015/09/30 00:00 [pmc-release] AID - 1417620112 [pii] AID - 201417620 [pii] AID - 10.1073/pnas.1417620112 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):4044-9. doi: 10.1073/pnas.1417620112. Epub 2015 Mar 16.