Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), a leading cause of death by an infectious disease globally, has no efficacious vaccine. Antibodies are implicated in M. tuberculosis control, but the mechanisms of action remain poorly understood. We assembled a library of monoclonal antibodies (mAb) and screened for M. tuberculosis-restrictive activity in mice, identifying protective antibodies targeting diverse antigens. To dissect the mechanism of mAb-mediated M. tuberculosis restriction, we optimized a protective lipoarabinomannan-specific mAb, generating Fc variants. In vivo analysis of these Fc variants revealed a role for Fc-effector function in M. tuberculosis restriction. Restrictive Fc variants altered distribution of M. tuberculosis across innate immune cells. Single-cell transcriptomics highlighted distinctly activated pathways within innate immune cell subpopulations, identifying early activation of neutrophils as a key signature of mAb-mediated M. tuberculosis restriction. Therefore, antibody-mediated restriction of M. tuberculosis is associated with reorganization of the tissue-level immune response to infection and depends on the collaboration of antibody Fab and Fc.
Authors
- Mohui Wei (ORCID: https://orcid.org/0000-0001-5609-450X)
- Patricia S. Grace (ORCID: https://orcid.org/0000-0002-4604-0943)
- Camille Locht (ORCID: https://orcid.org/0000-0001-7295-7336)
- Gunilla Källenius (ORCID: https://orcid.org/0000-0002-8921-0551)
- Lisa A. Cavacini (ORCID: https://orcid.org/0000-0003-1417-8339)
- Richard D. Cummings (ORCID: https://orcid.org/0000-0002-8918-5034)
- Christopher Sundling (ORCID: https://orcid.org/0000-0002-6138-690X)
- Alok Choudhary (ORCID: https://orcid.org/0000-0002-2933-9812)
- Andrew Julian Vickers (ORCID: https://orcid.org/0000-0003-1525-6503)
- Brooke A. Fenderson
- Joshua M. Peters (ORCID: https://orcid.org/0000-0001-9163-6706)
- Megan K. Proulx (ORCID: https://orcid.org/0000-0002-9524-8302)
- Abraham Pinter (ORCID: https://orcid.org/0000-0002-3262-3304)
- Aaron S. Wallace (ORCID: https://orcid.org/0000-0003-2264-3229)
- Christopher M. Sassetti (ORCID: https://orcid.org/0000-0001-6178-4329)
- Bryan D. Bryson (ORCID: https://orcid.org/0000-0003-1716-6712)
- Rajko Reljić (ORCID: https://orcid.org/0000-0003-4351-8355)
- Matthew D. Slein (ORCID: https://orcid.org/0000-0001-8288-787X)
- Jaimie Sixsmith
- Arturo Casadevall (ORCID: https://orcid.org/0000-0002-9402-9167)
- Edward B. Irvine (ORCID: https://orcid.org/0000-0002-8185-6454)
- Sarah M. Fortune (ORCID: https://orcid.org/0000-0001-7565-9975)
- Tanya R. McKitrick (ORCID: https://orcid.org/0000-0002-1312-6089)
- J. Ernst (ORCID: https://orcid.org/0000-0001-9951-6207)
- Galit Alter
- Richard Lu
- Corinne Luedeman
Institutions
- Rutgers, The State University of New Jersey (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Johns Hopkins University (US)
- University of Massachusetts Chan Medical School (US)
- University of California, San Francisco (US)
- Ragon Institute of MGH, MIT and Harvard (US)
Publication Details
- Journal
- Immunity
- Published
- 2025-05-30
- DOI
- https://doi.org/10.1016/j.immuni.2025.05.004
- Citations
- 6
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 8.38
Funders
- Bill and Melinda Gates Foundation
- Ragon Institute of MGH, MIT and Harvard
- National Institutes of Health
- Office of Extramural Research, National Institutes of Health