c-Myb Regulates the T-Bet-Dependent Differentiation Program in B Cells to Coordinate Antibody Responses

Dana Piovesan; Jessica Tempany; Andrea Di Pietro; Inge Baas; Callisthenis Yiannis; Kristy O'Donnell; Yunshun Chen; Victor Peperzak; Gabrielle T Belz; Charles R Mackay; Gordon K Smyth; Joanna R Groom; David M Tarlinton; Kim L Good-Jacobson

doi:10.1016/j.celrep.2017.03.060

c-Myb Regulates the T-Bet-Dependent Differentiation Program in B Cells to Coordinate Antibody Responses

Cell Rep. 2017 Apr 18;19(3):461-470. doi: 10.1016/j.celrep.2017.03.060.

Affiliations

¹ 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; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
² Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
³ 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.
⁴ Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁵ Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Immunology and Pathology, Monash University, Prahan, VIC 3004, Australia.
⁶ Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
⁷ Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; The Department of Mathematics and Statistics, University of Melbourne, Parkville, VIC 3010, Australia.
⁸ Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Immunology and Pathology, Monash University, Prahan, VIC 3004, Australia.
⁹ 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; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: kim.jacobson@monash.edu.

PMID: 28423310
DOI: 10.1016/j.celrep.2017.03.060

Abstract

Humoral immune responses are tailored to the invading pathogen through regulation of key transcription factors and their networks. This is critical to establishing effective antibody-mediated responses, yet it is unknown how B cells integrate pathogen-induced signals to drive or suppress transcriptional programs specialized for each class of pathogen. Here, we detail the key role of the transcription factor c-Myb in regulating the T-bet-mediated anti-viral program. Deletion of c-Myb in mature B cells significantly increased serum IgG2c and CXCR3 expression by upregulating T-bet, normally suppressed during Th2-cell-mediated responses. Enhanced expression of T-bet resulted in aberrant plasma cell differentiation within the germinal center, mediated by CXCR3 expression. These findings identify a dual role for c-Myb in limiting inappropriate effector responses while coordinating plasma cell differentiation with germinal center egress. Identifying such intrinsic regulators of specialized antibody responses can assist in vaccine design and therapeutic intervention in B-cell-mediated immune disorders.

Keywords: B cells; CXCR3; T-bet; c-Myb; germinal center; immunoglobulin; plasma cell.

Publication types

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

MeSH terms

Animals
Antibody Affinity
Antibody Formation / immunology*
B-Lymphocytes / cytology*
B-Lymphocytes / immunology*
Cell Differentiation*
Female
Gene Deletion
Gene Expression Regulation
Germinal Center / cytology
Germinal Center / metabolism
Humans
Male
Mice
Plasma Cells / cytology
Plasma Cells / metabolism
Proto-Oncogene Proteins c-myb / deficiency
Proto-Oncogene Proteins c-myb / metabolism*
Receptors, CXCR3 / metabolism
Syndecan-1 / metabolism
T-Box Domain Proteins / metabolism*
Transcription, Genetic

Substances

Cxcr3 protein, mouse
Proto-Oncogene Proteins c-myb
Receptors, CXCR3
Syndecan-1
T-Box Domain Proteins
T-box transcription factor TBX21