Tissue-resident memory T cells (TRM cells) remain in tissues after infection and help the body respond more rapidly upon subsequent encounters with a pathogen. Previous studies in mice have shown that these cells disappear relatively quickly from the lungs. It therefore remained unclear how long TRM cells can persist in human lungs and what role lung-draining lymph nodes play in maintaining immune memory.
Scientists from the La Jolla Institute for Immunology in the United States studied T cells from the lungs and their draining lymph nodes in 40 people. Based on the T-cell receptor (TCR) repertoire, the researchers determined which pathogens individual T cells recognize.
This approach allowed researchers to study large numbers of T cells specific to different common pathogens and compare their distribution between the lungs and lymph nodes.
The researchers found that respiratory pathogen-specific TRM cells can persist in human lungs for several months to several years. Thus, pulmonary T-cell memory in humans proved considerably more durable than might be expected based on studies in mice.
In addition, the same T-cell clones were only rarely found simultaneously in the lungs and their draining lymph nodes. This observation does not support the mouse model, in which lymph nodes serve as the main reservoir of memory cells that maintain the lung population.
Distinct Clones of Memory T Cells Accumulate in the Lungs
The researchers analyzed about 600,000 lung T cells and about 330,000 T cells from lung-draining lymph nodes from 40 people with no recent infections who were medically eligible for surgical lung resection for early-stage lung cancer. Comparison of T-cell receptor sequences showed that individual memory T-cell clones accumulated much more strongly in the lungs than in the lymph nodes. The 10% most abundant clonotypes accounted for 51% of CD4+ and 70% of CD8+ T cells in the lungs.
A substantial proportion of highly expanded lung TCR clonotypes were not detected in the lymph nodes, while the similarity between the TCR repertoires of the two tissues remained low. These findings were confirmed in an independent group of people without cancer.
These data indicate that, even without recent infection, human lungs contain a strongly expanded pool of individual memory T-cell clones that persist directly within lung tissue.
TRM Cells Predominantly Persist in the Human Lungs
TRM cells were the predominant CD4+ and CD8+ T cell type in human lungs. These TRM cells showed extensive clonal expansion: the 10% most abundant clones accounted for more than 46% of CD4+ and 50% of CD8+ TRM cells. This indicates selective accumulation of certain antigen-specific TRM cells in the lungs.
Comparison with lung-draining lymph nodes showed that more than 80% of lung TRM cell clonotypes were not detected there. Conversely, more than 50% of lymph node TRM cell clonotypes were clonally related to lung T cells. Thus, most TRM cells persist directly within lung tissue; unlike in mice, lymph nodes are not their main reservoir in humans.
A Significant Proportion of Lung T Cells Recognize Common Pathogens
The researchers identified which pathogens lung T cells recognize. To do this, they combined their own experimental data, obtained by stimulating peripheral blood cells from donor pools with peptide pools from nine common human pathogens, with published TCR databases. They also generated a catalog of more than 45,000 CD4+ T-cell TCRs specific to common pathogens. More than 99% of these TCRs had not previously been described.
As a result, the researchers determined the specificity of about 11% of CD4+ and 15% of CD8+ lung T cells. These data show that a substantial proportion of memory T cells in the lungs recognize common pathogens.
The Lungs Are a Long-Term Reservoir of CD4+ Memory T Cells Formed After Previous Infections
In most participants, the researchers detected CD4+ memory T cells in the lungs specific to five common respiratory viruses:
- SARS-CoV-2;
- influenza A virus;
- parainfluenza virus;
- respiratory syncytial virus;
They also detected CD4+ memory T cells recognizing herpesviruses (CMV and EBV), the causative agent of pertussis (Bordetella pertussis), and the fungus Aspergillus fumigatus.
The number of TRM cells varied substantially between individuals but was not associated with a specific pathogen, age, sex, body mass index, smoking status, or vaccination status.
A substantial number of TRM cells specific to several respiratory viruses persisted without evidence of recent infection. These findings indicate that the human lungs serve as a long-term reservoir of CD4+ TRM cells formed following previous infections.
CD8+ Memory T Cells Specific to Different Viruses Persist in the Lungs
The researchers detected CD8+ memory T cells in the lungs of participants that were specific to:
- cytomegalovirus;
- Epstein-Barr virus;
- SARS-CoV-2;
- influenza A virus.
The researchers also identified a subset of CD8+ TRM cells with high expression of HLA-DR and other MHC class II molecules – a feature typically associated with recent T-cell activation. However, the participants had no recent infections, and 39 of the 40 participants had not been vaccinated during the preceding 90 days. This indicates that such cells can accumulate in the lungs independently of recent activation.
The frequency of these pathogen-specific CD8+ TRM cells varied substantially between participants, with no particular pathogen associated with a higher proportion. Participant characteristics were also not associated with TRM frequency. Age was the exception: older individuals had more frequently detected SARS-CoV-2-specific CD8+ TRM cells.
TRM Cells Persist in the Human Lungs for Years
Analysis of repeat lung tissue samples from six individuals, obtained at intervals ranging from seven weeks to nearly six years, confirmed the long-term persistence of TRM cells. On average, at least half of the CD4+ and CD8+ TRM cell clones were detected again in repeat samples from the same individual. In one participant, more than half of the most abundant TRM clones persisted for more than five years.
Clones of effector memory T cells detected in the lungs were also found among memory T cells in the blood. In contrast, most TRM cell clones were not detected in the blood. This indicates that TRM cells persist long-term directly in the lungs and that their population is largely not maintained by cells from the circulation.
TRM cell clones persisted in the lungs over time, with their relative abundance remaining similar, while the cells retained the characteristic features of tissue-resident memory T cells. This indicates long-term stability in both the composition of the TRM clone repertoire and its properties.
Clones that persisted or disappeared over time did not differ in TNFRSF9 and ENTPD1 activity, which are associated with TCR signaling. This indicates that long-term persistence of TRM cells in the lungs does not require continuous T-cell receptor stimulation.
Reference
Human lungs maintain tissue-resident memory T cells against a broad spectrum of pathogens
