NK cell-macrophage interactions in granulomas correlate with limited tuberculosis pathology

Abstract

Development of novel vaccines and treatment approaches against tuberculosis are hampered by limited knowledge of what constitutes a protective immune response against Mycobacterium tuberculosis (Mtb). Granulomas are organized immune aggregates that form in the lung in response to mycobacterial infection and are an important site of pathogen-host interaction. The composition and cellular microenvironment within the granuloma impacts the bacterial control capacity. To identify protective responses in granulomas, imaging mass cytometry was used to study archived lung tissue from low dose Mtb-infected non-human primates presenting with various levels of disease. This approach revealed that granuloma composition is correlated with the severity of lung pathology. Granulomas of animals with limited lung pathology were enriched for NK cells showing increased interactions with tissue macrophages. This work improves our understanding of local immune interactions in the lung and how these correlate with severity of tuberculosis disease. Author summaryTuberculosis remains the deadliest infectious disease in the world with 10 million new infections and 1.5 million deaths annually. The existing vaccine is not effective enough to halt the tuberculosis epidemic. In order to develop an improved vaccine, more complete and detailed knowledge on the immune responses that can successfully protect against tuberculosis is required. Individuals that are exposed to Mycobacterium tuberculosis, the pathogen that causes tuberculosis disease, fall along a spectrum, with some individuals showing a strong innate capacity to protect against disease, while others fall ill. By studying these differences in a model organism, namely non-human primates, we can learn about protective immune responses. In primates with limited disease, the immune cell aggregates surrounding the bacteria in the lung contained more NK cells than were found in severe disease. In addition, interactions between NK cells and macrophages, cells that can eat bacteria, were seen a lot more in protected animals. This suggests that the interaction between NK cell and macrophages contributes to controlling tuberculosis disease, this knowledge can contribute to improved vaccine strategies.