Lung Immune Memory Lasts Longer Than in Mice: Human T-Cell Atlas Reshapes Our View of Respiratory Defenses

After a respiratory infection, how long can immune memory remain in the lungs? Previous mouse studies showed that tissue-resident memory T cells in the lungs decline rapidly, raising doubts about whether this local line of defense is destined to be short-lived. A human study published in *Nature Immunology* now presents a different picture: human lungs can retain T-cell clones associated with a range of pathogens over the long term, with some still identifiable after several years.

The La Jolla Institute for Immunology, the University of Liverpool, and other institutions analyzed non-tumor lung tissue from 40 participants aged 61 to 83. By combining single-cell transcriptomics with paired T-cell receptor sequencing, they created an immune atlas of the lungs and lung-draining lymph nodes. The researchers then used T-cell receptors as “molecular barcodes” for antigen recognition, referencing pathogen-specific receptors found in participants’ blood and existing databases to infer the possible targets recognized by more than 87,000 lung T cells.

The atlas showed that the lungs of most participants simultaneously contained tissue-resident memory T cells capable of recognizing multiple pathogens, including influenza A, SARS-CoV-2, parainfluenza, respiratory syncytial virus, and human metapneumovirus, as well as cytomegalovirus, Epstein–Barr virus, *Bordetella pertussis*, and *Aspergillus fumigatus*. This does not mean that every cell has been proven to prevent infection, but it shows that the immune experience preserved in the lungs is far more complex than the traces left by a single virus.

More direct evidence of durability came from 6 participants who underwent two lung surgeries at different times. The two samples were collected 7 to 304 weeks apart; the researchers found that a substantial proportion of CD4 and CD8 tissue-resident memory T cells shared the same receptor clones at both time points. In one participant with the longest interval—more than 5 years—over half of the originally highly expanded clones could still be found in the second sample, supporting the idea that some lung immune memory can be maintained locally over the long term.

The findings also highlight differences between humans and mice that cannot be ignored. Human lung-resident clones had limited overlap with T cells in lung-draining lymph nodes and blood, indicating that they do not primarily rely on continual replenishment by circulating cells. If the goal of a vaccine is to reduce severe respiratory infections, researchers may need to assess whether the vaccine can establish durable resident immunity in the lungs or other respiratory tissues, rather than inferring effectiveness solely from antibody and T-cell responses in the blood.

However, translating this finding into a vaccine assessment tool will not be easy. Lung tissue cannot be routinely obtained in the same way as blood, and more feasible alternative sampling methods and reliable surrogate markers remain to be established. The study itself did not directly compare how different vaccines shape these cells, nor did it prove that clone persistence necessarily equates to clinical protection.

The representativeness of the samples also limits how broadly the conclusions can be generalized. The main participants were all older white British people undergoing surgery to remove early-stage lung cancer. Although the analysis used visually normal tissue taken far from the tumors, it still cannot fully represent younger people, different populations, or healthy lungs. Long-term follow-up included only 6 people. The next step is to validate this atlas across a wider range of ages and clinical backgrounds, and to directly examine changes in lung T cells before and after vaccination and their relationship with infection risk.