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

Nat Immunol. 2022 Jan;23(1):86-98. doi: 10.1038/s41590-021-01077-y. Epub 2021 Nov 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / immunology
  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology
  • Antibody Formation / immunology
  • B-Lymphocytes / immunology*
  • Female
  • Germinal Center / immunology
  • Immunity, Humoral / immunology*
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic choriomeningitis virus / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Polycomb Repressive Complex 1 / immunology*
  • Proto-Oncogene Proteins / immunology*

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Bmi1 protein, mouse
  • Proto-Oncogene Proteins
  • Polycomb Repressive Complex 1