Intestinal tuft cell immune privilege enables norovirus persistence. Intestinal tuft cell immune privilege enables norovirus persistence

The persistent murine norovirus strain MNVCR6 is a model for human norovirus and enteric viral persistence. MNVCR6 causes chronic infection by directly infecting tuft cells, rare chemosensory epithelial cells. Although MNVCR6 induces functional MNV-specific CD8+ T cells, these lymphocytes fail to clear infection. To clarify 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 tuft cell reporter mice (Gfi1b-GFP). Surprisingly, some tuft cells partially resist JEDI CD8+ T cell-mediated killing – unlike Lgr5+ intestinal stem cells and extraintestinal tuft cells – despite seemingly normal antigen presentation. When targeting tuft cells, JEDI CD8+ T cells predominantly adopt a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. Importantly, JEDI CD8+ T cells neither clear nor prevent MNVCR6 infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen (e.g., GFP). Overall design: To investigate the effector function of JEDI CD8+ T cells in the colonic epithelium of mice targeting Gfi1b-GFP+ tuft cells or Lgr5-GFP+ stem cells

持续性鼠诺如病毒毒株MNVCR6是人类诺如病毒（human norovirus）与肠道病毒持续性感染的研究模型。MNVCR6通过直接感染簇细胞（tuft cell）——一类罕见的化学感应上皮细胞——引发慢性感染。尽管MNVCR6可诱导产生具有功能的MNV特异性CD8+ T细胞，但这类淋巴细胞无法清除感染。

为阐明簇细胞介导免疫逃逸的具体机制，我们通过将JEDI（Just EGFP Death Inducing）CD8+ T细胞过继转移至簇细胞报告小鼠（Gfi1b-GFP）体内，探究了簇细胞与CD8+ T细胞的相互作用。令人意外的是，尽管抗原呈递过程看似正常，但部分簇细胞可部分抵抗JEDI CD8+ T细胞介导的杀伤——这一表现与Lgr5阳性肠道干细胞及肠外簇细胞截然不同。

当靶向簇细胞时，JEDI CD8+ T细胞主要呈现组织驻留记忆表型（T resident memory phenotype），其效应功能与细胞毒性均显著下降，从而使得簇细胞得以存活。

尤为重要的是，尽管JEDI CD8+ T细胞靶向的是非病毒抗原（如GFP，即绿色荧光蛋白（green fluorescent protein）），但它们既无法清除也无法阻止结肠内的MNVCR6感染——而结肠正是病毒持续性感染的主要发生部位。

整体实验设计：为探究靶向Gfi1b-GFP阳性簇细胞或Lgr5阳性干细胞的小鼠结肠上皮中JEDI CD8+ T细胞的效应功能。