Airway Immune Signature May Predict Tuberculosis Progression Risk

Tuberculosis remains difficult to predict and prevent, despite widespread exposure worldwide. An estimated quarter of the global population has been infected with Mycobacterium tuberculosis, yet only a small fraction develops active disease, and routine tests cannot identify who will progress. Early, local immune events in the lung are thought to be decisive but are rarely captured by blood-based assessments. New findings demonstrate how diverging airway immune programs may determine progression versus control of infection.

Researchers at The Francis Crick Institute examined immune activity directly in the lower airways to define early determinants of disease. Collaborating with clinicians at University Hospitals of Leicester NHS Trust, the team analyzed bronchoalveolar lavage samples from recent household contacts of people with pulmonary tuberculosis. Using bulk RNA sequencing, single-cell RNA sequencing, and flow cytometry, they constructed a cell- and gene-level view of the initial host response to Mycobacterium tuberculosis in the lung.

The study identified two distinct trajectories. In individuals who developed active tuberculosis, airways were dominated by neutrophils, with approximately half of these cells activating a type I interferon–linked gene program. Neutrophils broadly expressed CXCL8, indicating a feed-forward loop that could amplify pulmonary inflammation. In parallel, T cells in neutrophil-rich airways showed signs of exhaustion and cell death, consistent with impaired bacterial control. By contrast, individuals who controlled infection had T cells that were neither hyperactivated nor exhausted and instead expressed regulatory and stem-like gene signatures.

Similar airway immune patterns were observed in analyses of published nonhuman primate datasets and in prior murine work from the same group, supporting the relevance of these early programs across models. Together, the findings suggest that the balance between inflammatory neutrophils and functional T cells in the airways may be a key determinant of clinical outcome. 

The work, published in Nature Immunology on May 18, 2026, points to opportunities to identify early immune signatures that could help stratify risk and to explore targeted interventions that favor durable, protective T cell responses, including approaches that modulate CXCL8–CXCR2–mediated neutrophil trafficking.

“TB diagnosis is challenging since the bacteria can be hard to detect, and current tests cannot determine whether an infected person is likely to become ill with TB. If we can find a way to identify these immune signatures early in people who have been infected, we might be able to predict who is at risk,” said Anne O'Garra, whose lab at The Francis Crick Institute studies how the immune system responds to infection.

“It's about getting the balance right. The immune system must control the bacterial infection without causing excessive inflammation and damage to the lungs. And that balance likely determines who stays well. In another recent study from the lab, we showed that type I interferon signaling drives neutrophil swarming in the lungs, limiting the interactions between T cells and macrophages that are needed to control TB,” said Will Branchett, first author at The Francis Crick Institute.

Related Links
The Francis Crick Institute
University Hospitals of Leicester NHS Trust