LONDON — The Francis Crick Institute, in collaboration with clinicians at University Hospitals of Leicester NHS Trust, published a study in Nature Immunology in 2026 that investigated immune responses to Mycobacterium tuberculosis. The study analyzed bronchoalveolar lavage samples from recent household contacts of individuals with pulmonary tuberculosis.

Researchers found that the airways of people who developed active tuberculosis were dominated by neutrophils. Half of these neutrophils had activated genes linked to type I interferon signaling and produced high levels of CXCL8, a molecule that recruits more neutrophils to the lung. Will Branchett, a researcher, observed evidence of exhaustion and cell death in the T-cells from these patients. "We saw evidence of exhaustion and cell death in the T cells," Branchett said.

In contrast, people who controlled the infection exhibited T-cells that were not highly activated or exhausted. "There, the T cells weren't highly activated, but they weren't exhausted either," Branchett said. These T-cells expressed genes linked to regulation and a stem-like state. "Instead, these cells expressed genes linked to regulation and a more 'stem-like' state, suggesting they can persist and respond over a longer period and thus remain ready to fight the infection," he said.

Current tuberculosis tests cannot determine if an infected person will become ill with the disease. "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," said Anne O'Garra, a researcher. The team utilized bulk RNA sequencing, single-cell RNA sequencing, and flow cytometry to analyze the immune cells. They identified similar immune cell response patterns in published studies of tuberculosis in non-human primates and in previous studies from O'Garra's lab involving mice.

"The big question has always been what distinguishes people who control the infection from those who don't," O'Garra said. A 2010 study in Nature, which included O'Garra, identified an immune signature in the blood of individuals with active tuberculosis, associating it with type I interferon. An estimated quarter of the global population has been infected with Mycobacterium tuberculosis, but only 5-10% develop active tuberculosis. Drugs like CXCR2 inhibitors, which target CXCL8 function, are currently in trials for other lung conditions. Branchett plans to establish an independent research group to further study tuberculosis infection mechanisms.