Intestinal tuft cell immune privilege enables norovirus persistence.

The persistent murine norovirus strain MNV^CR6 is a model for human norovirus and enteric viral persistence. MNV^CR6 causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory epithelial cells. Although MNV^CR6 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 MNV^CR6 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. Editor's summary: Norovirus is a major cause of acute foodborne illness that can also lead to persistent infections. Specialized chemosensory epithelial cells called tuft cells are the target cell for murine norovirus, but how chronic infections are established remains unclear. Using mice with CD8⁺ T cells bearing a fluorescent protein-specific T cell receptor, Strine et al. found that intestinal tuft cells are intrinsically resistant to CD8⁺ T cell–mediated killing compared with other gut epithelial cells. Tuft cell–mediated immune evasion from CD8⁺ T cells enabled norovirus persistence in the colon. These findings indicate that intestinal tuft cells represent an immune-privileged niche that is intrinsically resistant to T cell responses. —Claire Olingy [ABSTRACT FROM AUTHOR]