Targeting BMI-1 in B cells restores effective humoral immune responses and controls chronic viral infection

Andrea Di Pietro, Jack Polmear, Lucy Cooper, Timon Damelang, Tabinda Hussain, Lauren Hailes, Kristy O’Donnell, Vibha Udupa, Tian Mi, Simon Preston, Areen Shtewe, Uri Hershberg, Stephen J. Turner, Nicole L. La Gruta, Amy W. Chung, David M. Tarlinton, Christopher D. Scharer, Kim L. Good-Jacobson

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

Ineffective antibody-mediated responses are a key characteristic of chronic viral infection. However, our understanding of the intrinsic mechanisms that drive this dysregulation are unclear. Here, we identify that targeting the epigenetic modifier BMI-1 in mice improves humoral responses to chronic lymphocytic choriomeningitis virus. BMI-1 was upregulated by germinal center B cells in chronic viral infection, correlating with changes to the accessible chromatin landscape, compared to acute infection. B cell-intrinsic deletion of Bmi1 accelerated viral clearance, reduced splenomegaly and restored splenic architecture. Deletion of Bmi1 restored c-Myc expression in B cells, concomitant with improved quality of antibody and coupled with reduced antibody-secreting cell numbers. Specifically, BMI-1-deficiency induced antibody with increased neutralizing capacity and enhanced antibody-dependent effector function. Using a small molecule inhibitor to murine BMI-1, we could deplete antibody-secreting cells and prohibit detrimental immune complex formation in vivo. This study defines BMI-1 as a crucial immune modifier that controls antibody-mediated responses in chronic infection.

Original languageEnglish
Pages (from-to)86-98
Number of pages13
JournalNature Immunology
Volume23
Issue number1
DOIs
Publication statusPublished - Jan 2022

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