Pathogenic role for CD101-negative neutrophils in the type I interferon-mediated immunopathogenesis of tuberculosis.

Neutrophils are vital for immunity against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), yet their heterogeneous nature suggests a complex role in TB pathogenesis. Here, we identify two distinct neutrophil populations based on CD101 expression, highlighting their divergent roles in TB. CD101-negative (CD101) neutrophils, which resemble immature, pro-inflammatory granulocytes, exhibit reduced Mtb phagocytosis compared to their mature, CD101-positive (CD101) counterparts. Our findings reveal that type I interferons (IFN-Is) suppress neutrophil Mtb uptake and drive the recruitment of CD101 neutrophils to the lungs. Infiltration of these cells promotes Mtb extracellular persistence, exacerbates epithelial damage, and impairs surfactant production. Furthermore, we demonstrate that granulocyte colony-stimulating factor (G-CSF) and chemokine receptor CXCR2 are essential for the pulmonary accumulation of CD101 neutrophils. Our study uncovers a pathogenic role for CD101 neutrophils in TB and highlights the IFN-I-dependent recruitment of this functionally compromised immature neutrophil as a driver of TB immunopathogenesis.