Intestinal tuft cell immune privilege enables norovirus persistence.

The persistent murine norovirus strain MNV is a model for human norovirus and enteric viral persistence. MNV causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory epithelial cells. Although MNV 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 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.