Journal article
Targeting BMI-1 in B cells restores effective humoral immune responses and controls chronic viral infection
A Di Pietro, J Polmear, L Cooper, T Damelang, T Hussain, L Hailes, K O’Donnell, V Udupa, T Mi, S Preston, A Shtewe, U Hershberg, SJ Turner, NL La Gruta, AW Chung, DM Tarlinton, CD Scharer, KL Good-Jacobson
Nature Immunology | NATURE PORTFOLIO | Published : 2022
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 imp..
View full abstractGrants
Awarded by Monash University
Funding Acknowledgements
We thank J. Groom (Walter and Eliza Hall Institute), I. Parish (Peter MacCallum Cancer Centre), C. Zaph and J. Rossjohn for critical reading of this manuscript and/or discussions; M. Pellegrini (Walter and Eliza Hall Institute), M. Degli-Esposti (Monash University) and A. Papa (Monash University) for generously providing, respectively, LCMV stocks, IL-2 and c-Myc antibody; J. Sun and members of the Good-Jacobson laboratory for technical assistance; O. Chernyavskiy and the staff of Monash Micro Imaging for the provision of instrumentation training and technical support; Monash FlowCore, Bioinformatics and Animal Research Platforms; and MHTP Medical Genomics Facility. This work was supported by a Bellberry-Viertel Senior Medical Research Fellowship (K.L.G.-J.); National Health and Medical Research Council (NHMRC) Career Development Fellowships 1108066 (K.L.G.-J.) and 1140509 (A.W.C.); American Association of Immunologists Careers in Immunology Fellowship and Travel for Techniques program (A.D.P. and K.L.G.-J.); Australian Research Council Future Fellowship FT170100174 and Discovery Project DP200102776, NHMRC Ideas grant 1182086 (N.L.L.G.); NHMRC Program grant 1054925 and Investigator award 1175411 (D.M.T. and K.O.D.); Australian Research Council Discovery Project DP170102020 and NHMRC Ideas grant 1183478 (S.J.T.); Monash University Biomedicine Discovery Institute Scholarship (L.C.); Monash University Scholarship for Excellence (J.P.); Monash University Graduate Scholarship and Monash International Postgraduate Research Scholarship (T.H.); Postgraduate Scholarship from the Bonn University -Melbourne University joining PhD program (V.U.); National Institutes of Health P01 AI106697 and the European Union's Horizon 2020 Research and Innovation program 825821 (U.H. and A.S.). The contents of this document can under no circumstances be regarded as reflecting the position of the European Union.