Hidden Army of Tissue-Resident Memory T Cells Defends Human Lungs Against a Broad Range of Pathogens
核心洞察
A Nature Immunology study led by La Jolla Institute for Immunology and University of Liverpool provides the first comprehensive look at tissue-resident memory T cells (搜索) (TRM cells) in human lungs.
Researchers analyzed more than 87,000 lung TRM cells from 40 participants and found these cells can target viruses, bacteria, and even deadly fungal pathogens.
Human lung TRM cells persist for months or years, unlike mouse TRM cells, which undergo quick attrition, underscoring the value of studying human immune cells directly.
New research led by scientists at La Jolla Institute for Immunology (LJI) and University of Liverpool (UOL) provides the first comprehensive look at how a hidden immune cell army defends the vast, vulnerable tissue of the human lungs. The Nature Immunology study shows that human lung tissue serves as a "reservoir" for a large number of tissue-resident memory T cells (搜索) (TRM cells), which stand ready to combat a surprising range of viruses, bacteria, and even deadly fungal pathogens.
The findings carry significant implications for vaccine development, as the LJI team hopes to guide the creation of vaccines that boost TRM cell responses to deliver more effective, longer-lasting immunity against severe respiratory infections.
Why This Immune Cell Army Stayed Hidden
The researchers found that these TRM cells reside only in the lungs, which means they do not show up in blood samples. While these TRM cells can live for years in human lung tissue, they do not persist in mice, which are a common model in preclinical research.
"This study highlights the power of investigating immune cells from humans," said Pandurangan Vijayanand, M.D., Ph.D., study leader and LJI William K. Bowes Distinguished Professor.
How T Cells Specialize to Save Lives
T cells are notable for their ability to specialize. Almost every individual T cell in the body responds to one molecular marker of disease, called an antigen, from a specific pathogen. A T cell that targets SARS-CoV-2 (搜索) infection, for example, would not be able to target an influenza virus infection.
TRM cells specialize even further, adapting to defend one kind of tissue. In recent years, LJI scientists have discovered that TRM cells serve as a vital line of defense against cancers. Vijayanand and his colleagues are focused on defining how TRM cells potentially respond to infections in human lungs.
For their new study, the researchers examined more than 87,000 lung TRM cells from 40 human study participants. These participants ranged in age from 61 to 83, which gave the scientists an opportunity to understand how past vaccines and lifelong exposure to pathogens shape TRM cells in the lungs.
A Broad Arsenal Against Respiratory Threats
To determine what these 87,000 TRM cells were looking for, LJI Postdoctoral Fellow Vicente Fajardo-Rosas, Ph.D., and Aquib Ehtram, Ph.D., spearheaded cutting-edge sequencing and analysis work in the Vijayanand Lab. Lung tissue samples and extensive clinical metadata were obtained from participants enrolled in the Target Lung study, led by University of Liverpool Professor Christian Ottensmeier, M.D., Ph.D.
The researchers discovered that human lung tissue is home to a valuable reservoir of T cells that can target a huge range of infections. Many study participants had TRM cells ready to respond to five common respiratory viruses: influenza type A (搜索), SARS-CoV-2 (搜索), parainfluenza virus, respiratory syncytial virus (搜索) (RSV), and metapneumovirus (MPV).
Many participants also had lung T cells that could target two common herpesviruses—cytomegalovirus (CMV) and Epstein Barr virus (EBV)—as well as the potentially deadly bacterium Bordetella pertussis (搜索), which causes whooping cough. Some study participants even had TRM cells that could respond to a common fungus, Aspergillus fumigatus (搜索), which can cause life-threatening infections in immunocompromised patients.
This stunning array of TRM cell responses highlights the body's ability to build up immunity over time.
Implications for Vaccine Research
The findings have important implications for future vaccine research. As Vijayanand notes, TRM cell responses observed in lung tissue are not seen in T cells that circulate in the blood. This means that vaccine researchers may need to examine lung T cells, and not just blood samples, to understand how to boost immunity directly in the respiratory system.
"An important next step is to study how vaccination impacts TRM cells in the lungs," said Vijayanand. "We need to assess more samples, including samples from donors who recently received vaccines."
The new study also reveals a key biological difference between human subjects and mouse models of disease. In previous studies, researchers found TRM cells in mouse lungs, but these cells undergo quick attrition. Vijayanand and his colleagues found that human TRM cells remain in the lungs for months or even years.