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Published on: April 29, 2020
Intestinal tuft cell immune privilege enables norovirus persistence
Madison S Strine1, Eric Fagerberg1, Patrick W Darcy2
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Abstract:
The persistent murine norovirus strain MNVCR6 is a model for human norovirus and enteric viral persistence. MNVCR6 causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory epithelial cells. Although MNVCR6 induces functional MNV-specific CD8+ T cells, these lymphocytes fail to clear infection. To examine how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8+ T cells by adoptively transferring JEDI (just EGFP death inducing) CD8+ T cells into Gfi1b-GFP tuft cell reporter mice. Unexpectedly, some intestinal tuft cells partially resisted JEDI CD8+ T cell-mediated killing-unlike Lgr5+ intestinal stem cells and extraintestinal tuft cells-despite seemingly normal antigen presentation. When targeting intestinal tuft cells, JEDI CD8+ T cells predominantly adopted a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. JEDI CD8+ T cells neither cleared nor prevented MNVCR6 infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen. Ultimately, we show that intestinal tuft cells are relatively resistant to CD8+ T cells independent of norovirus infection, representing an immune-privileged niche that can be leveraged by enteric microbes.
Insights
Intestinal tuft cells resist CD8+ T cell killing, creating a viral immune-privileged niche. This resistance allows persistent norovirus infection by limiting T cell effector function.
Area of Science:
- Immunology
- Microbiology
- Gastroenterology
Background:
- Murine norovirus (MNVCR6) causes chronic infection by targeting intestinal tuft cells.
- CD8+ T cells are induced but fail to clear MNVCR6 infection.
- Tuft cells are rare chemosensory epithelial cells in the intestine.
Purpose of the Study:
- Investigate how intestinal tuft cells promote immune escape from CD8+ T cells.
- Determine the interaction between tuft cells and CD8+ T cells during viral infection.
- Examine the susceptibility of intestinal tuft cells to T cell-mediated killing.
Main Methods:
- Adoptive transfer of JEDI CD8+ T cells into Gfi1b-GFP tuft cell reporter mice.
- Analysis of T cell phenotype and cytotoxic capacity.
- Assessment of viral clearance and persistence in the colon.
Main Results:
- Intestinal tuft cells exhibited partial resistance to CD8+ T cell-mediated killing.
- CD8+ T cells targeting tuft cells developed a resident memory phenotype with reduced effector function.
- MNVCR6 infection persisted in the colon despite CD8+ T cell presence.
Conclusions:
- Intestinal tuft cells represent an immune-privileged niche resistant to CD8+ T cells, independent of norovirus.
- This tuft cell resistance mechanism can be exploited by enteric microbes for persistence.
- Understanding this interaction is crucial for developing strategies against persistent enteric viral infections.
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