Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction

Patricia S Grace; Joshua M Peters; Jaimie Sixsmith; Richard Lu; Edward B Irvine; Corinne Luedeman; Brooke A Fenderson; Andrew Vickers; Matthew D Slein; Tanya McKitrick; Mo-Hui Wei; Richard D Cummings; Aaron Wallace; Lisa A Cavacini; Alok Choudhary; Megan K Proulx; Christopher Sundling; Gunilla Källenius; Rajko Reljic; Joel D Ernst; Arturo Casadevall; Camille Locht; Abraham Pinter; Christopher M Sassetti; Bryan D Bryson; Sarah M Fortune; Galit Alter

doi:10.1016/j.immuni.2025.05.004

Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction

Immunity. 2025 Jun 10;58(6):1586-1597.e5. doi: 10.1016/j.immuni.2025.05.004. Epub 2025 May 30.

Authors

Patricia S Grace¹, Joshua M Peters², Jaimie Sixsmith³, Richard Lu⁴, Edward B Irvine¹, Corinne Luedeman⁴, Brooke A Fenderson⁴, Andrew Vickers³, Matthew D Slein⁴, Tanya McKitrick⁵, Mo-Hui Wei⁵, Richard D Cummings⁵, Aaron Wallace⁶, Lisa A Cavacini⁶, Alok Choudhary⁷, Megan K Proulx⁸, Christopher Sundling⁹, Gunilla Källenius⁹, Rajko Reljic¹⁰, Joel D Ernst¹¹, Arturo Casadevall¹², Camille Locht¹³, Abraham Pinter⁷, Christopher M Sassetti⁸, Bryan D Bryson², Sarah M Fortune¹⁴, Galit Alter¹⁵

Affiliations

¹ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
² Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
⁵ Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁶ MassBiologics of the University of Massachusetts Medical School, Boston, MA, USA.
⁷ Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
⁸ Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
⁹ Division of Infectious Diseases, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
¹⁰ Institute for Infection and Immunity, St. George's University, London, UK.
¹¹ Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹² Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹³ University of Lille, CNRS, Inserm, CHU Lille Institut Pasteur de Lille, U1019-URM9017_Center for Infection and Immunity of Lille, 5900 Lille, France.
¹⁴ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: sfortune@hsph.harvard.edu.
¹⁵ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA. Electronic address: galter@partners.org.

PMID: 40449485
PMCID: PMC12476823 (available on 2026-05-30)
DOI: 10.1016/j.immuni.2025.05.004

Abstract

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.

Keywords: Fc effector function; Mycobacterium tuberculosis; alveolar macrophage; humoral immunity; lung immunity; monoclonal antibody; neutrophil; opsinophagocytosis.

MeSH terms

Animals
Antibodies, Bacterial* / immunology
Antibodies, Monoclonal* / immunology
Antigens, Bacterial / immunology
Humans
Immunity, Innate
Immunoglobulin Fab Fragments* / immunology
Immunoglobulin Fc Fragments* / immunology
Lipopolysaccharides / immunology
Mice
Mice, Inbred C57BL
Mycobacterium tuberculosis* / immunology
Neutrophils / immunology
Tuberculosis* / immunology

Substances

Antibodies, Monoclonal
Antibodies, Bacterial
Immunoglobulin Fab Fragments
Immunoglobulin Fc Fragments
Lipopolysaccharides
lipoarabinomannan
Antigens, Bacterial

Abstract

MeSH terms

Substances

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