CD4-mediated immunity shapes neutrophil-driven tuberculous pathology

Area of Science:

• Immunology
• Pathology
• Microbiology

Background:

• Tuberculosis lesions exhibit diverse structures, including necrotic granulomas and alveolitis.
• Alveolitis is linked to prior immunity in human tuberculosis, but underlying mechanisms are unclear.

Approach:

• Modeled divergent tuberculosis lesion structures in C3HeB/FeJ mice.
• Utilized quantitative imaging, single-cell RNA sequencing (scRNAseq), and flow cytometry.
• Conducted immune cell depletion studies at various infection stages.

Key Points:

• Absence of prior immunity leads to dysregulated neutrophil recruitment and necrotic granulomas in Mycobacterium tuberculosis infection.
• Prior immunity promotes rapid T cell recruitment/activation, macrophage activation, and reduced late neutrophil responses.
• Neutrophils are essential for initiating and propagating necrosis, while early CD4 T cell responses inhibit necrosis.

Conclusions:

• Prior immunity fundamentally determines tuberculosis lesion structure and pathogenesis.
• Understanding these immune-driven mechanisms offers insights for novel tuberculosis prevention and treatment strategies.