Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction

Area of Science:

• Immunology
• Microbiology
• Infectious Diseases

Background:

• Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a global health threat with no effective vaccine.
• Antibody roles in controlling M. tuberculosis are recognized, but mechanisms are poorly understood.

Purpose of the Study:

• To investigate the mechanisms of antibody-mediated restriction of Mycobacterium tuberculosis.
• To identify the roles of antibody structure, specifically Fc-effector function, in controlling M. tuberculosis infection.

Main Methods:

• Screening of a monoclonal antibody (mAb) library for M. tuberculosis-restrictive activity in a mouse model.
• Optimization of a lipoarabinomannan-specific mAb, generating Fc variants to dissect Fc-effector function.
• In vivo analysis of Fc variants using single-cell transcriptomics to assess immune cell responses and M. tuberculosis distribution.

Main Results:

• Protective antibodies targeting diverse antigens were identified.
• Fc-effector function was crucial for antibody-mediated restriction of M. tuberculosis.
• Restrictive Fc variants altered M. tuberculosis distribution among innate immune cells.
• Early neutrophil activation was identified as a key signature of mAb-mediated restriction.

Conclusions:

• Antibody-mediated restriction of M. tuberculosis involves reorganization of the tissue-level immune response.
• Effective control of M. tuberculosis by antibodies depends on the collaborative function of antibody Fab and Fc domains.
• Neutrophil activation is a critical early event in antibody-mediated control of M. tuberculosis infection.