LA JOLLA, CA—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 new Nature Immunology study shows that human lung tissue serves as a "reservoir" for a large number of tissue-resident memory T cells (TRM cells). These cells stand ready to combat a surprising range of viruses, bacteria, and even deadly fungal pathogens.
How has this army remained hidden for so long?
The researchers found that these TRM cells reside only in the lungs, which means they don't show up in blood samples. And while these TRM cells can live for years in human lung tissue, they don't persist in mice, which are a common model in preclinical research.
"This study highlights the power of investigating immune cells from humans," says study leader LJI William K. Bowes Distinguished Professor Pandurangan Vijayanand, MD., Ph.D.
With this new window into human immunology, the LJI team hopes to guide the development of vaccines that boost TRM cell responses to deliver more effective, longer-lasting immunity against severe respiratory infections.
How T cells save lives
T cells are amazing for their ability to specialize. Almost every individual T cell in your body responds to one molecular marker of disease, called an antigen, from a specific pathogen. A T cell that targets SARS-CoV-2 infection, for example, wouldn't be able to target an influenza virus infection.
TRM cells specialize even further. These cells adapt to defending one kind of tissue. In recent years, LJI scientists have discovered that TRM cells serve as a vital line of defense against cancers [See studies in Nature Immunology , Journal of Experimental Medicine , and Cell Reports ].
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 study 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.
Since individual T cells respond to specific targets, the scientists wanted to know: What were these 87,000 TRM cells looking for?
TRM cells jump into action
To find answers, 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 Christians Ottensmeier, MD, 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, SARS-CoV-2, parainfluenza virus, respiratory syncytial virus (RSV), and metapneumovirus (MPV). Many study 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, which causes whooping cough. Some study participants even had TRM cells that could respond to a common fungus, Aspergillus fumigatus, which can cause life-threatening infections in immunocompromised patients.
This stunning array of TRM cell responses highlights the body's amazing ability to build up immunity over time.
Advancing vaccine research
The findings also 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," says 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. And yet Vijayanand and his colleagues found that human TRM cells remain in the lungs for months or even years.
This difference means it may be critical to look more closely at human lung tissue samples for future TRM cell research and preclinical vaccine studies.
Additional authors of the study, "The human lung is a reservoir of tissue-resident memory T cells against a broad spectrum of pathogens," include Isabel Marchand-Casas, Serena J. Chee, Monalisa Mondal, Celia Ferrández Alaminos, Francisco Emmanuel Castañeda-Castro, Zubin Roy, Lindsey Chudley, Michael Shackcloth, Judith Cave, Aiman Alzetani, Edwin Woo, Elizabeth Phillips, Simon Mallal, Alba Grifoni, Benjamin J. Schmiedel, Alessandro Sette, Bjoern Peters, and Christian H. Ottensmeier.
This study was supported by the National Institutes of Health (grants U19AI118626, S10OD025052, S10 RR027366, S10 OD026929), and the William K. Bowes Jr Foundation. Sample collection was supported by the North West and South Central Research Delivery Networks, National Institute of Health Research, UK.
