Anti-apoptotic proteins BCL-2, MCL-1 and A1 summate collectively to maintain survival of immune cell populations both in vitro and in vivo

Emma M Carrington; Yifan Zhan; Jamie L Brady; Jian-Guo Zhang; Robyn M Sutherland; Natasha S Anstee; Robyn L Schenk; Ingela B Vikstrom; Rebecca B Delconte; David Segal; Nicholas D Huntington; Philippe Bouillet; David M Tarlinton; David Cs Huang; Andreas Strasser; Suzanne Cory; Marco J Herold; Andrew M Lew

doi:10.1038/cdd.2017.30

Anti-apoptotic proteins BCL-2, MCL-1 and A1 summate collectively to maintain survival of immune cell populations both in vitro and in vivo

Cell Death Differ. 2017 May;24(5):878-888. doi: 10.1038/cdd.2017.30. Epub 2017 Mar 31.

Authors

Emma M Carrington^{1

2}, Yifan Zhan^{1

2}, Jamie L Brady^{1

2}, Jian-Guo Zhang^{1

2}, Robyn M Sutherland^{1

2}, Natasha S Anstee^{1

2}, Robyn L Schenk^{1

2}, Ingela B Vikstrom¹, Rebecca B Delconte^{1

2}, David Segal^{1

2}, Nicholas D Huntington^{1

2}, Philippe Bouillet^{1

2}, David M Tarlinton^{1

2

3}, David Cs Huang^{1

2}, Andreas Strasser^{1

2}, Suzanne Cory^{1

2}, Marco J Herold^{1

2}, Andrew M Lew^{1

2

4}

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
² Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
³ Department of Immunology & Pathology, Monash University, Melbourne, VIC 3004, Australia.
⁴ Department of Microbiology & Immunology, University of Melbourne, Parkville, VIC 3010, Australia.

Abstract

Survival of various immune cell populations has been proposed to preferentially rely on a particular anti-apoptotic BCL-2 family member, for example, naive T cells require BCL-2, while regulatory T cells require MCL-1. Here we examined the survival requirements of multiple immune cell subsets in vitro and in vivo, using both genetic and pharmacological approaches. Our findings support a model in which survival is determined by quantitative participation of multiple anti-apoptotic proteins rather than by a single anti-apoptotic protein. This model provides both an insight into how the sum of relative levels of anti-apoptotic proteins BCL-2, MCL-1 and A1 influence survival of T cells, B cells and dendritic cells, and a framework for ascertaining how these different immune cells can be optimally targeted in treatment of immunopathology, transplantation rejection or hematological cancers.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
B-Lymphocytes / cytology
B-Lymphocytes / drug effects
B-Lymphocytes / immunology
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / cytology
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
Cell Survival
Dendritic Cells / cytology
Dendritic Cells / drug effects
Dendritic Cells / immunology
Flow Cytometry
Gene Expression Regulation / immunology*
Immunity, Innate
Immunophenotyping
Mice
Mice, Inbred C57BL
Mice, Transgenic
Minor Histocompatibility Antigens / genetics*
Minor Histocompatibility Antigens / immunology
Models, Immunological*
Myeloid Cell Leukemia Sequence 1 Protein / genetics*
Myeloid Cell Leukemia Sequence 1 Protein / immunology
Organ Specificity
Proto-Oncogene Proteins c-bcl-2 / genetics*
Proto-Oncogene Proteins c-bcl-2 / immunology
Signal Transduction
Sulfonamides / pharmacology

Substances

Antineoplastic Agents
BCL2-related protein A1
Bridged Bicyclo Compounds, Heterocyclic
Mcl1 protein, mouse
Minor Histocompatibility Antigens
Myeloid Cell Leukemia Sequence 1 Protein
Proto-Oncogene Proteins c-bcl-2
Sulfonamides
Bcl2 protein, mouse
venetoclax