A Safe-Haven for Intestinal Viruses

When viruses infect a cell, they set off alarm bells in the body. Immune cells start to notice that the infected cell doesn’t quite look normal, and when they realize that the cell has been compromised by a foreign invader, they try to destroy it.

Despite these security systems, some viruses seem to avoid triggering their host’s defenses. Norovirus, for example, is a “stomach bug” that can cause vomiting and diarrhea after infecting specialized intestinal tuft cells. These cells are relatively rare and are designed to detect parasites using the clumps of bristles at their tips. When norovirus manages to infiltrate these cells, the virus tends to survive longer and cause chronic infection.

“They’re a really enigmatic and cool cell type,” said Craig Wilen, an immunologist at Yale University who first described tuft cells as a norovirus target in 2018.¹ “How does this really rare infected cell type pump out tons of virus and totally evade the immune system?”

Now, his team may have part of the answer. In a study published in Science Immunology, they showed in mice that intestinal tuft cells have “immune privilege.”² Even though antiviral CD8+ T cells recognize these cells, they do not kill them. Their findings could explain why norovirus chooses to hide out in these cells, making infections much worse.

CD8+ T cells are an important immune soldier tasked with killing infected cells. To study whether these cytotoxic cells could kill tuft cells, the researchers engineered uninfected tuft cells to express enhanced green fluorescent protein (EGFP) and introduced just EGFP death-inducing (JEDI) CD8+ T cells that are engineered to have an especially potent reaction to target cells expressing the fluorescent protein.³ To Wilen’s surprise, almost half of the tuft cells survived this attack.

“No matter what you do to turbocharge all the T cells, the tuft cells still find a way to evade them,” Wilen said. “It’s like they don’t even care that the T cell response is raging.”

The problem wasn’t that the T cells were lazy. When Wilen’s team marked a rare intestinal stem cell population with the fluorescent protein, the JEDI T cells decimated their target. Even though JEDI T cells traveled to the intestinal tuft cells, once they arrived at their target, they exhibited limited activity. They didn’t look dysfunctional, like T cells that are tamped down by a tumor, but they downregulated genes that are required to multiply and release molecules that destroy the tuft cells. 

Previous studies have reported similar T cell evasion by quiescent stem cells that downregulate molecules on their surfaces, such as major histocompatibility complexes, a system that allows  cells to display pieces of viral protein to trigger an immune response.⁴ However, the researchers confirmed that the tuft cells did not alter their expression of these antigen presentation molecules. “There’s nothing else about them that screams ‘abnormal,’” Wilen said.

“I’ve always wondered about this, because it struck me as somewhat unexpected that this virus chooses to replicate exclusively in this one very rare cell type,” said Jakob von Moltke, an immunologist at the University of Washington who was not involved in the study.  “[The researchers] addressed a really important question.” However, he noted that while the team cleverly used tools designed for cancer research to show that intestinal tuft cells intrinsically avoid immune detection, the question of how the cells accomplish this remains unanswered.

Understanding how intestinal tuft cells avoid CD8+ T cells could improve treatments for norovirus, but first, Wilen’s team needs to figure out whether their observations in mouse models translate to humans. “We don’t necessarily know for sure what role tuft cells play in human virus infection,” Wilen said. Recent research in monkeys and in humans shows that persistent norovirus infections target enteroendocrine cells in the intestines, which are closely related to intestinal tuft cells, so Wilen’s team is studying whether this cell type also evades the immune system.^5,6

Tuft cells aren’t only in the intestines. In this study, Wilen’s team found that tuft cells in a few other parts of the body, such as those living in the salivary gland and gallbladder, were not as savvy as the intestinal varieties and were easily destroyed by JEDI T cells. However, Wilen thinks that there might be immune-privileged tuft cells beyond the gut, where they could offer a foothold for diseases. “It’s a common theme across various sites that tuft cells have this ability to become cancerous,” said von Moltke. Wilen thinks that the immune evading properties of intestinal tuft cells could help lethal tuft cell cancers avoid CD8+ T cells in other organs such as the lungs.

“Figuring this out is important for immunotherapy and for tuft cell-mediated diseases,” Wilen said.

References

1. Wilen C, et al. Tropism for tuft cells determines immune promotion of norovirus pathogenesis. Science. 2018;360(6385):204-208.
2. Strine M, et al. Intestinal tuft cell immune privilege enables norovirus persistence. Sci Immunol. 2024;9(93):eadi7038.
3. Agudo J, et al. GFP-specific CD8 T cells enable targeted cell depletion and visualization of T-cell interactions. Nat Biotechnol. 2015;33(12):1287-1292.
4. Agudo J, et al. Quiescent tissue stem cells evade immune surveillance. Immunity. 2018;48(2):271-285.e5
5. Rimkute I, et al. A non-human primate model for human norovirus infection. Nat Microbiol. 2024;9(3):776-786.
6. Green KY, et al. Human norovirus targets enteroendocrine epithelial cells in the small intestine. Nat Commun. 2020;11(1):2759.