IRF4 Activity Is Required in Established Plasma Cells to Regulate Gene Transcription and Mitochondrial Homeostasis
Michael Sze Yuan Low,
Erica J. Brodie,
Pasquale L. Fedele,
Yang Liao,
George Grigoriadis,
Andreas Strasser,
Axel Kallies,
Simon N. Willis,
Julie Tellier,
Wei Shi,
Sarah Gabriel,
Kristy O’Donnell,
Catherine Pitt,
Stephen L. Nutt,
David Tarlinton
Affiliations
Michael Sze Yuan Low
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, VIC, Australia; Monash Haematology, Monash Health, 246 Clayton Road, Clayton 3168, VIC, Australia; Department of Immunology and Pathology, Monash University, 89 Commercial Road, Melbourne 3004, VIC, Australia; School of Clinical Sciences at Monash Health, Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton 3168, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne 3010, VIC, Australia
Erica J. Brodie
Department of Immunology and Pathology, Monash University, 89 Commercial Road, Melbourne 3004, VIC, Australia
Pasquale L. Fedele
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, VIC, Australia; Monash Haematology, Monash Health, 246 Clayton Road, Clayton 3168, VIC, Australia; School of Clinical Sciences at Monash Health, Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton 3168, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne 3010, VIC, Australia
Yang Liao
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne 3010, VIC, Australia; School of Computing and Information Systems, The University of Melbourne, Melbourne 3010, VIC, Australia
George Grigoriadis
Monash Haematology, Monash Health, 246 Clayton Road, Clayton 3168, VIC, Australia; School of Clinical Sciences at Monash Health, Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton 3168, VIC, Australia
Andreas Strasser
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne 3010, VIC, Australia
Axel Kallies
The Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne, Melbourne 3010, VIC, Australia
Simon N. Willis
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne 3010, VIC, Australia
Julie Tellier
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne 3010, VIC, Australia
Wei Shi
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne 3010, VIC, Australia; School of Computing and Information Systems, The University of Melbourne, Melbourne 3010, VIC, Australia
Sarah Gabriel
The Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne, Melbourne 3010, VIC, Australia
Kristy O’Donnell
Department of Immunology and Pathology, Monash University, 89 Commercial Road, Melbourne 3004, VIC, Australia
Catherine Pitt
Department of Immunology and Pathology, Monash University, 89 Commercial Road, Melbourne 3004, VIC, Australia
Stephen L. Nutt
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne 3010, VIC, Australia
David Tarlinton
Department of Immunology and Pathology, Monash University, 89 Commercial Road, Melbourne 3004, VIC, Australia; Corresponding author
Summary: The transcription factor interferon regulatory factor 4 (IRF4) is critical for the development, maintenance, and function of plasma cells. The mechanism by which IRF4 exerts its action in mature plasma cells has been elusive due to the death of all such cells upon IRF4 loss. While we identify apoptosis as a critical pathway for the death of plasma cells caused by IRF4 loss, we also determine that IRF4 did not regulate the intrinsic apoptotic pathway directly. By using an inducible IRF4 deletion system in the presence of the overexpression of anti-apoptotic BCL2, we identify genes whose expression is coordinated by IRF4 and that in turn specify plasma cell identity and mitochondrial homeostasis. : Plasma cells can provide lifelong immunity by the continued production of high-affinity, antigen-specific antibody. Low et al. reveal that the transcription factor IRF4 acts within established plasma cells to prevent apoptosis and maintain cellular identity and mitochondrial homeostasis. Keywords: antibody, metabolism, gene expression, myeloma, cell survival, humoral immunity, BLIMP1
