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.