The Histone Methyltransferase DOT1L Is Essential for Humoral Immune Responses
Liam Kealy,
Andrea Di Pietro,
Lauren Hailes,
Sebastian Scheer,
Lennard Dalit,
Joanna R. Groom,
Colby Zaph,
Kim L. Good-Jacobson
Affiliations
Liam Kealy
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Andrea Di Pietro
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Lauren Hailes
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Sebastian Scheer
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Lennard Dalit
Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
Joanna R. Groom
Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
Colby Zaph
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Kim L. Good-Jacobson
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Corresponding author
Summary: Histone modifiers are essential for the ability of immune cells to reprogram their gene expression during differentiation. The recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like) induces oncogenic gene expression in a subset of B cell leukemias. Despite its importance, its role in the humoral immune system is unclear. Here, we demonstrate that DOT1L is a critical regulator of B cell biology. B cell development is defective in Dot1lf/fMb1Cre/+ mice, culminating in a reduction of peripheral mature B cells. Upon immunization or influenza infection of Dot1lf/fCd23Cre/+ mice, class-switched antibody-secreting cells are significantly attenuated and germinal centers fail to form. Consequently, DOT1L is essential for B cell memory formation. Transcriptome, pathway, and histological analyses identified a role for DOT1L in reprogramming gene expression for appropriate localization of B cells during the initial stage of the response. Together, these results demonstrate an essential role for DOT1L in generating an effective humoral immune response.
