Zeb2 drives the formation of CD11c + atypical B cells to sustain germinal centers that control persistent infection.

Autor: Gao X; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australia., Shen Q; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australia.; Francis Crick Institute, London, UK., Roco JA; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australia., Dalton B; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australia., Frith K; Sydney Children's Hospital, Randwick, Australia.; School of Women's and Children's Health, UNSW Sydney, Sydney, Australia., Munier CML; Kirby Institute, UNSW Sydney, Sydney, Australia., Ballard FD; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australia., Wang K; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australia., Kelly HG; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australia., Nekrasov M; Australian Cancer Research Foundation Biomolecular Resource Facility, John Curtin School of Medical Research, The Australian National University, Canberra, Australia., He JS; ANU Centre for Therapeutic Discovery, John Curtin School of Medical Research, Australian National University, Canberra, Australia., Jaeger R; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australia., Carreira P; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australia., Ellyard JI; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australia., Beattie L; Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia., Enders A; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australia., Cook MC; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australia.; Cambridge Institute for Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK., Zaunders JJ; Centre for Applied Medical Research, St Vincent's Hospital, Sydney, New South Wales, Australia., Cockburn IA; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
Jazyk: angličtina
Zdroj: Science immunology [Sci Immunol] 2024 Mar 29; Vol. 9 (93), pp. eadj4748. Date of Electronic Publication: 2024 Mar 29.
DOI: 10.1126/sciimmunol.adj4748
Abstrakt: CD11c + atypical B cells (ABCs) are an alternative memory B cell lineage associated with immunization, infection, and autoimmunity. However, the factors that drive the transcriptional program of ABCs have not been identified, and the function of this population remains incompletely understood. Here, we identified candidate transcription factors associated with the ABC population based on a human tonsillar B cell single-cell dataset. We identified CD11c + B cells in mice with a similar transcriptomic signature to human ABCs, and using an optimized CRISPR-Cas9 knockdown screen, we observed that loss of zinc finger E-box binding homeobox 2 (Zeb2) impaired ABC formation. Furthermore, ZEB2 haplo-insufficient Mowat-Wilson syndrome (MWS) patients have decreased circulating ABCs in the blood. In Cd23 Cre/+ Zeb2 fl/fl mice with impaired ABC formation, ABCs were dispensable for efficient humoral responses after Plasmodium sporozoite immunization but were required to control recrudescent blood-stage malaria. Immune phenotyping revealed that ABCs drive optimal T follicular helper (T FH ) cell formation and germinal center (GC) responses and they reside at the red/white pulp border, likely permitting better access to pathogen antigens for presentation. Collectively, our study shows that ABC formation is dependent on Zeb2, and these cells can limit recrudescent infection by sustaining GC reactions.
Databáze: MEDLINE