微生物来源的肌苷程序保护CD8⁺ T细胞对新生儿流感的反应，这一成果由美国辛辛那提大学医学院Hitesh Deshmukh研究小组经过不懈努力而取得。2025年6月9日，国际知名学术期刊《细胞》发表了这一成果。

研究组证明，抗生素诱导的生态失调通过破坏核因子白介素3 （NFIL3）依赖的T细胞编程，损害了婴儿小鼠和人类的流感特异性CD8⁺ T细胞免疫。从机制上讲，课题组人员发现生态失调降低了肠道和循环肌苷水平，破坏了NFIL3对T细胞因子1 （TCF1）表达的表观遗传调控。这导致CD8⁺ T细胞增殖和分化的内在缺陷，效应反应减弱，组织驻留记忆细胞的形成受损。双歧杆菌定植恢复肠道和肺部肌苷水平，建立了特定的肠-肺代谢通讯途径。值得注意的是，补充肌苷可以挽救nfil3依赖的TCF1调控，增强CD8⁺ T细胞应答，并保护婴儿免受流感感染。他们的发现揭示了生命早期微生物群落如何形成抗病毒免疫，并确定肌苷是增强婴儿呼吸防御的治疗靶点。

研究人员表示，生命早期对呼吸道病毒感染的易感性仍然是一个主要的公共卫生问题，但其潜在机制尚不清楚。

附：英文原文

Title: Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns

Author: Joseph Stevens, Erica Culberson, Jeremy Kinder, Alicia Ramiriqui, Jerilyn Gray, Madeline Bonfield, Tzu-Yu Shao, Faris Al Gharaibeh, Laura Peterson, Shelby Steinmeyer, Emily M. Eshleman, Shikha Negi, William Zacharias, Gloria Pryhuber, Oindrila Paul, Shaon Sengupta, Theresa Alenghat, Sing Sing Way, Hitesh Deshmukh

Issue&Volume: 2025-06-09

Abstract: Early-life susceptibility to respiratory viral infections remains a major public health concern, yet the underlying mechanisms are poorly understood. We demonstrate that antibiotic-induced dysbiosis impairs influenza-specific CD8+ T cell immunity in infant mice and humans through the disruption of nuclear factor interleukin 3 (NFIL3)-dependent T cell programming. Mechanistically, we show that dysbiosis reduces intestinal and circulating inosine levels, disrupting NFIL3’s epigenetic regulation of T cell factor 1 (TCF1) expression. This leads to intrinsic defects in CD8+ T cell proliferation and differentiation, diminished effector responses, and impaired formation of tissue-resident memory cells. Bifidobacterium colonization restores intestinal and pulmonary inosine levels, establishing a specific pathway of gut-lung metabolic communication. Notably, inosine supplementation rescues NFIL3-dependent regulation of TCF1, enhancing CD8+ T cell responses and protection against influenza infection in dysbiotic infants. Our findings reveal how early-life microbial communities shape antiviral immunity and identify inosine as a therapeutic target for enhancing respiratory defenses in infants.

DOI: 10.1016/j.cell.2025.05.013

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00563-X