Immature neutrophils linked to rapid tuberculosis progression in macaques

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), can behave very differently from person to person: some people carry the bacterium with few or no symptoms, while others develop active, destructive disease. The innate immune system — the body’s first line of defense — is thought to play a key role in determining those outcomes, but which early responses protect and which promote disease is not well understood. In new work led by Julien Lemaître, researchers used a nonhuman primate model, the cynomolgus macaque, to look closely at one part of innate immunity: neutrophils. Neutrophils are white blood cells that can both attack microbes and drive damaging inflammation, so the team asked whether different kinds of neutrophils appear during infection and whether those differences track with how the disease unfolds. To do this they infected macaques with Mtb and followed them over time, sorting animals by clinical, bacteriological and imaging measures into groups that rapidly progressed to active TB, called “fast progressors,” and those that developed minimal or delayed disease, called “slow progressors.” The goal was to find immune changes that accompany either control of the infection or progression to active TB.

To search for clues, the team combined several approaches. Animals were evaluated by clinical and bacteriological measures and by PET/CT scan parameters to classify disease course. Blood and tissue samples were analyzed for gene activity and cell types. Transcriptomic analysis revealed signatures of type I interferons and neutrophil degranulation that were characteristic of animals that rapidly progressed to active TB but were absent in slow progressors. At the cellular level, unsupervised mass cytometry analysis showed the emergence in blood of immature neutrophils identified as CD101+ CD10- specifically in fast progressing animals. Functional tests on circulating neutrophils indicated they could influence TNF-α production and the cytotoxic activity of CD8 T cells, and this modulation required direct contact. In lung lesions, neutrophil infiltration of granuloma was greater in fast progressors and concentrated in lymphocyte-rich regions of lesions, pointing to a physical association between neutrophils and T cells in sites of disease.

Taken together, these findings suggest a chain of events in which certain neutrophil subpopulations expand during uncontrolled infection and help drive the inflammatory environment of active TB. The presence of type I interferon and neutrophil degranulation signatures in fast progressors links particular molecular signals to the appearance of immature, CD101+ CD10- neutrophils in the blood and to heavier neutrophil infiltration in lung granulomas. The observation that neutrophils can modify TNF-α production and CD8 T cell cytotoxicity in a contact-dependent manner suggests neutrophils may actively shape adaptive immunity in ways that reduce control of Mtb and amplify inflammation. While the study was conducted in cynomolgus macaques, the results provide new insights into why some infections progress while others remain contained and point to neutrophil subtypes and neutrophil–T cell interactions as potential biomarkers or targets for host-directed interventions to limit TB progression.