As the immune system ages, it enters a state of chronic, low-grade inflammation called ‘inflammaging’.In the brain, inflammaging is especially damaging. Immune cells that normally clear toxic amyloid-beta, a protein that can clump together to form the plaques characteristic of Alzheimer’s disease, instead become dysfunctional, fuelling the neuroinflammation that drives the disease.So a vaccine that stimulates the immune system would seem an unlikely treatment for a disease driven by brain inflammation. But a new study in Communications Medicine suggests the century-old tuberculosis vaccine Bacillus Calmette-Guérin (BCG) does the opposite: rather than boosting immunity, it retrains innate immune cells within the ageing brain.Training the immune systemThe study is based on trained immunity, a phenomenon in which certain vaccines give innate immune cells a long-lasting memory, making them more effective against unrelated threats. Unlike antibodies, which recognise specific germs, trained immunity makes the innate immune system respond more effectively to many different threats. Clinicians have also long observed that bladder cancer patients treated with BCG have a lower incidence of dementia.To test whether this immune training extends to the central nervous system, researchers at the Massachusetts General Hospital, U.S., enrolled 23 older adults, roughly half with and half without cerebrospinal fluid biomarkers of Alzheimer’s disease. Participants received two BCG doses a month apart and researchers tracked blood and the fluid over the following year.Measuring this fluid is hard.“From a 10-ml blood draw, you get about 10 million immune cells. During a lumbar puncture, you get about 10,000,” said Mahesh Chandra Kodali, a neuroscientist and study co-author at Massachusetts General Hospital.But even with so few cells, the team found that monocytes — the predominant immune cells in cerebrospinal fluid in the study — switched on genes linked to a faster, more alert immune response, mirroring similar changes in the bloodstream.“The findings strikingly reveal that trained immunity-like responses can occur within” the central nervous system, which is normally shielded from much of the body’s immune activity, Soumen Basak, an immunologist at the National Institute of Immunology, Delhi, said.Notably, when the team reexposed these cells to BCG itself in the lab, they didn’t respond more strongly than before. But they did respond more strongly to an unrelated bacterial molecule called lipopolysaccharide (LPS) — suggesting the vaccine had put cells on general alert, rather than teaching them to recognise BCG alone, Dr. Kodali said.Immune cells respond differently depending on the tissue they inhabit. Cells in the liver, for example, react differently to the same signal than similar cells in the lungs. So Dr. Basak suggested the brain may similarly shape how these cells respond.