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

Abstract

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^-ve) neutrophils, which resemble immature, pro-inflammatory granulocytes, exhibit reduced Mtb phagocytosis compared to their mature, CD101-positive (CD101^+ve) counterparts. Our findings reveal that type I interferons (IFN-Is) suppress neutrophil Mtb uptake and drive the recruitment of CD101^-ve 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^-ve neutrophils. Our study uncovers a pathogenic role for CD101^-ve neutrophils in TB and highlights the IFN-I-dependent recruitment of this functionally compromised immature neutrophil as a driver of TB immunopathogenesis.