Post Doctoral researcher
Walter and Eliza Hall Institute of Medical Research
The distinct apoptotic identity of dendritic cells offers novel targets for immunosupression
Emma M Carrington1,2, Jian-Guo Zhang1,2, Robyn M Sutherland1,2, Ingela B Vikstrom1,2, Jamie L Brady1,2, Priscilla Soo1, David Vremec1, Cody Allison1,2, Erinna F Lee1,2, W Douglas Fairlie1,2, Philippe Bouillet1,2, Stephanie Grabow1,2, Eleonora Ottina3, Marco J Herold1,2, Marc Pellegrini1,2, David C. S. Huang1,2, David M Tarlinton1,2, Andreas Strasser1,2, Andrew M Lew1,2,4, Yifan Zhan1,2.
1Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; 2Department of Medical Biology, The University of Melbourne, Parkville, Australia; 3Department of Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria; 4Department of Microbiology and Immunology, The University of Melbourne, Parkville, Australia
Aims: Dendritic cells (DC) are heterogeneous, comprising of subsets with functional specializations that orchestrate immunity as well as immunopathology. Thus, DCs are an attractive target for immune intervention. We investigated the molecular control of survival (especially the anti-apoptotic BCL-2 family members) of two main DC subsets: plasmacytoid DCs (pDCs) and conventional DCs (cDCs).
Methods: Conventional and plasmacytoid dendritic cells were purified from mice and expression of anti-apoptotic Bcl-2 family members (BCL-2, BCL-XL, BCL-W, MCL-1 and A1) assessed at mRNA and protein levels. Mice genetically deficient in individual proteins, or treated with mimetic inhibitors targeting selective anti-apoptotic Bcl-2 family members, were used to dissect functional requirements for DC survival.
Results: Compared with cDCs, pDCs expressed higher BCL-2, lower A1 and similar MCL-1 and BCL-XL levels. Neither subset expressed appreciable amounts of BCL-W protein. Transgenic over-expression of BCL-2 increased the pDC pool size in vivo with only little impact on cDCs. With a view to immune intervention, we tested clinically relevant BCL-2 inhibitors and found that ABT-199 (a 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.
Conclusions: We reveal that cDCs and pDCs have different molecular requirements for cell survival. We therefore advocate that this apoptotic identity avails the antagonism of selective BCL-2 family members for achieving immunosuppression pertaining to these distinct DC subsets.
Australian National Health and Medical Research Council. Juvenile Diabetes Research Foundation. Rebecca L. Cooper Foundation. The Leukemia and Lymphoma Society. Victorian State Government Operational Infrastructure Support. Australian Government NHMRC IRIIS.
15:30 - 17:00
|Immunology||The distinct apoptotic identity of dendritic cells offers novel targets for immunosupression||Room 111-112|