How targeting killer T cells in the lungs could lead to immunity against respiratory viruses [Salk Institute]

Researchers led by Salk Institute professor Susan Kaech, PhD, have discovered how memory T cells that are responsible for long-term immunity in the lungs can be reactivated more easily than previously thought. The team’s studies, published in the Journal of Experimental Medicine, provide new insights into how lung immune cells respond to viral infections and could feasibly aid in the development of universal vaccines for influenza and SARS-CoV-2.

“Inside our lungs exist long-lived killer T cells that recognize specific viruses and protect us against re-infection, should we encounter the virus again,” said Kaech, who is director of Salk’s NOMIS Center for Immunobiology and Microbial Pathogenesis. “Our results have elucidated the manner by which these cells ‘see’ the virus upon re-infection and provide rapid immunity. It also may help us understand long-term immunity as it relates to coronavirus.”

The investigators reported on their studies in a paper titled, “Tissue-resident memory T cell reactivation by diverse antigen-presenting cells imparts distinct functional responses.”

At first exposure to bacteria, or viruses such as influenza, one type of immune cell, known as killer T cells, destroy infected cells to prevent the spread of the disease. Once the pathogen is cleared, these experienced killer T cells (also called killer memory T cells) remain in our body for the long term, and “remember” previous invaders. These killer memory T cells enable our immune systems to more rapidly respond to a second attack and effectively provide long-term protective immunity against the invader. “CD8+ tissue-resident memory T cells (TRM cells) are poised at the portals of infection and provide long-term protective immunity,” the authors wrote. This is a fundamental concept behind vaccination.

Scientists know a lot about how killer memory T cells get reactivated in lymphoid organs (such as lymph nodes). Immune messenger cells called dendritic cells present fragments of the virus to the killer memory T cell, to license their killer function. But prior studies had not examined this interaction in vital organs, such as the lung. Given that the lung is a frequent entry site for pathogens such as influenza and coronavirus, the team set out to confirm whether the same, long-held view also applied to killer memory T cells that reside in the lungs.

Kaech and study first author, then graduate student Jun Siong Low, assumed that dendritic cells would also be required to reactivate lung-resident killer memory T cells to fight a second viral attack. To test this they deleted various types of messenger cells one at a time in mice to see if the killer memory T cells would still recognize a second influenza infection. To help visualize the results the researchers used a green fluorescent reporter protein to make the killer memory T cells glow if they recognized the virus. Each time the researchers deleted a specific cell type, the killer memory T cells in the lungs continued to glow.

“At first, our results were disappointing because it didn’t seem like our experiments were working; the killer memory T cells in the lungs continued to recognize the virus after the deletion of many different messenger cell types,” said Low, now a postdoctoral fellow at the Institute for Research in Biomedicine (IRB) at the Università della Svizzera Italiana, in Switzerland. “Soon, we realized that these lung-resident killer memory T cells were special because they were not reliant on any single type of messenger cell. Instead, they could ‘see’ the second influenza infection through a variety of different messenger cells, including non-immune cells like lung epithelial cells, which was a remarkably exciting finding.”

Lung-specific CD8 killer T cells (blue) in lung tissue (green) surrounded by dendritic lung cells (red). [Salk Institute]

This ability did seem to be specific to the killer memory T cells in the lung. When the researchers looked again at the lymph nodes, they found that dendritic cells known as CD11+ antigen-presenting cells (APCs) were needed to reactivate the killer memory T cells in the event of a second viral attack. This suggests that the anatomical location of the killer memory T cells dictates how they become reactivated, which challenges the long-held belief that this cell type always requires dendritic cells for reactivation.

“The present study resolves the conundrum between the requirement for APC licensing and rapid memory T cell activation by discovering that the dependence on CD11c+ DCs for memory CD8+ T cell reactivation is location dependent,” the authors concluded. “CD8+ TRM cells are tissue sentinels that provide protective antigen-specific and bystander-inflammatory responses and we propose that their reactivation promiscuity by multiple types of APCs allows for more rapid and sensitive pathogen sensing … Together, this work uncovers fundamental differences in the activation kinetics, mechanics, and effector responses between CD8+ memory T cells in peripheral vs. lymphoid organs, revealing a novel tissue-specific paradigm for the reactivation of memory CD8+ T cells.”

From left: Susan Kaech and Jun Siong Low, wearing a shirt commemorating the 1,846 days he spent conducting his graduate work on viral infections. [Salk Institute]

The results may reshape the existing model of killer memory T cell activation. Because lung-resident killer memory T cells can be quickly reactivated by nearly any cell type at the site of pathogen entry, identifying vaccines that can create these lung-resident killer memory T cells will likely be critical for superior immunity to viral infections of the lungs.

“We will take this knowledge into our next study, where we will examine whether lung-resident killer memory T cells form after a coronavirus infection,” said Kaech, holder of the NOMIS chair. “Since not all infections induce killer memory T cells, we will determine if these cells form after a coronavirus infection and whether they can be protective against future coronavirus infections.”

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