Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Laboratory of Mucosal Immunology, Rockefeller University, New York, NY, USA.
Sci Immunol. 2024 Mar 22;9(93):eadi7038. doi: 10.1126/sciimmunol.adi7038.
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.
持续存在的鼠诺如病毒株 MNV 是人类诺如病毒和肠道病毒持续感染的模型。MNV 通过直接感染肠簇状细胞（罕见的化学感觉上皮细胞）导致慢性感染。尽管 MNV 诱导了功能性的 MNV 特异性 CD8 T 细胞，但这些淋巴细胞未能清除感染。为了研究簇状细胞如何促进免疫逃逸，我们通过将 JEDI（仅 EGFP 诱导死亡）CD8 T 细胞过继转移到 Gfi1b-GFP 簇状细胞报告小鼠中，来研究簇状细胞与 CD8 T 细胞的相互作用。出乎意料的是，尽管簇状细胞似乎正常地呈递抗原，但与 Lgr5 肠干细胞和肠外簇状细胞不同，一些肠簇状细胞部分抵抗了 JEDI CD8 T 细胞介导的杀伤。当靶向肠簇状细胞时，JEDI CD8 T 细胞主要采用 T 驻留记忆表型，效应和细胞毒性能力降低，从而使簇状细胞得以存活。尽管针对的是一种与病毒无关的抗原，但 JEDI CD8 T 细胞既不能清除也不能预防结肠中的 MNV 感染，而结肠是病毒持续存在的部位。最终，我们表明，肠簇状细胞对 CD8 T 细胞具有相对的抗性，而与诺如病毒感染无关，这代表了一种免疫特权的生态位，可以被肠道微生物利用。
