Stevens Joseph, Culberson Erica, Kinder Jeremy, Ramiriqui Alicia, Gray Jerilyn, Bonfield Madeline, Shao Tzu-Yu, Al Gharaibeh Faris, Peterson Laura, Steinmeyer Shelby, Eshleman Emily M, Negi Shikha, Zacharias William, Pryhuber Gloria, Paul Oindrila, Sengupta Shaon, Alenghat Theresa, Way Sing Sing, Deshmukh Hitesh
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Infectious Disease, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Cell. 2025 Aug 7;188(16):4239-4256.e19. doi: 10.1016/j.cell.2025.05.013. Epub 2025 Jun 9.
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.
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，但其潜在机制仍知之甚少。我们证明，抗生素诱导的微生物群失调通过破坏核因子白细胞介素3（NFIL3）依赖的T细胞编程，损害幼鼠和人类的流感特异性CD8 T细胞免疫。从机制上讲，我们发现微生物群失调会降低肠道和循环中的肌苷水平，破坏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、效应反应减弱以及组织驻留记忆细胞形成受损。双歧杆菌定植可恢复肠道和肺部的肌苷水平，建立肠道与肺部代谢通讯的特定途径。值得注意的是，补充肌苷可挽救NFIL3对TCF1的依赖性调节，增强CD8 T细胞反应，并保护失调的婴儿免受流感感染。我们的研究结果揭示了生命早期微生物群落如何塑造抗病毒免疫力，并确定肌苷是增强婴儿呼吸道防御的治疗靶点。
