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Could AT2 Cells Improve Outcome of Respiratory Viral Infections — Including SARS-CoV-2?

Published on June 30, 2021 in Cornerstone Blog · Last updated 5 months 3 weeks ago


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By Nancy McCann

The findings:

Type II alveolar cells (AT2), a major cell type infected by SARS-CoV-2, possess unique immunologic properties and appear to play a role in improving the outcome of respiratory viral infections.

Why it matters:

Researchers at Children’s Hospital of Philadelphia discovered that a specific type of lung cell exhibits unconventional immune properties and may contribute to the outcome of respiratory viral infections. The researchers focused on AT2 cells, which are non-immune cells of the lung that are critical for basic lung health and tissue repair after lung injury. They found that AT2 cells express high levels of major histocompatibility complex II (MHC-II), an important immune system trigger, and that AT2 MHC-II expression appears to confer an appreciable advantage in the outcome of respiratory viral infection.

Who conducted the study:

A University of Pennsylvania MD/PhD candidate in the Eisenlohr Lab at CHOP, Sushila “Annie” Toulmin, was the first author, and investigator Laurence Eisenlohr, VMD, PhD, was senior author. Several CHOP colleagues and University of Pennsylvania collaborators also contributed to this paper.

How they did it:

To better understand the role of AT2 MHC-II, the researchers analyzed mouse and human AT2 cells and found, despite being non-immune cells, AT2s express MHC-II at levels similar to specialized immune cells such as B cells, dendritic cells, and macrophages, also known as the “professional antigen presenting cells.” They also found that in AT2 cells, MHC-II expression is activated independent of the presence of inflammatory signals — which are otherwise thought to be required by all other cells outside of the immune system in order to express MHC-II — suggesting that MHC-II expression by AT2s is regulated by unique mechanisms.

Given the role of MHC-II in initiating an immune response, the researchers then examined the role of AT2 MHC-II in protecting the lungs from respiratory disease. To test this, the researchers worked with a murine model with an AT2-specific deletion of MHC-II. Under normal conditions, the health of the model did not seem to be affected by the deletion of MHC-II; they did not have substantial alterations in lung immune cells or develop spontaneous respiratory disease, and the lung tissue was comparably healthy to mice with functional AT2 MHC-II. The researchers concluded that MHC-II does not seem to be required to maintain healthy lung immune or physiologic homeostasis. However, when the mice were exposed to influenza A virus and Sendai virus, the mouse model with AT2 MHC-II deletion had higher morbidity and mortality than those with intact MHC-II, implying that it does contribute to improved outcomes during lung infection.

They also found that AT2 cells are capable of presenting antigen via MHC-II at homeostasis and in the setting of infection; however, overall compared to the specialized “professional antigen presenting cells,” AT2 cells exhibit very limited antigen presentation capacity.

Quick thoughts:

“This study shows that MHC-II expression is regulated in a unique way in AT2 cells, which has important implications for the health of lungs when faced with infection,” Dr. Eisenlohr said. “Although future studies will need to explore the reasons why this combination of high MHC-II expression but limited antigen presentation occurs in AT2 cells, we propose that this system allows AT2s to enhance immune responses without triggering excessive T cell activation that could be damaging to the delicate gas exchange surface of the lung.”

Where the study was published:

The study appears in Nature Communications.

What’s next?

Future studies will seek to understand whether alterations in AT2 MHCII expression or function contribute to the broad variation in outcome of lung diseases in humans, particularly SARS-CoV-2 infection, as AT2s are the main cell type infected with this virus in the human lung.

Want to learn more?

Check out this CHOP press release.