Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction

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

Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction

Patricia S Grace et al. Immunity. 2025.

. 2025 Jun 10;58(6):1586-1597.e5.

doi: 10.1016/j.immuni.2025.05.004. Epub 2025 May 30.

Authors

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests G.A. is a founder of SeromYx Systems.

Update of

Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction.
Grace PS, Peters JM, Sixsmith J, Lu R, Luedeman C, Fenderson BA, Vickers A, Slein MD, Irvine EB, McKitrick T, Wei MH, Cummings RD, Wallace A, Cavacini LA, Choudhary A, Proulx MK, Sundling C, Källenius G, Reljic R, Ernst JD, Casadevall A, Locht C, Pinter A, Sasseti CM, Bryson BD, Fortune SM, Alter G. Grace PS, et al. bioRxiv [Preprint]. 2024 Oct 11:2024.10.07.617070. doi: 10.1101/2024.10.07.617070. bioRxiv. 2024. Update in: Immunity. 2025 Jun 10;58(6):1586-1597.e5. doi: 10.1016/j.immuni.2025.05.004. PMID: 39416184 Free PMC article. Updated. Preprint.

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Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction

Affiliations

Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical