Medical College of Wisconsin
CTSIResearch InformaticsREDCap

Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns. Cell 2025 Aug 07;188(16):4239-4256.e19

Date

06/11/2025

Pubmed ID

40494345

Pubmed Central ID

PMC12335363

DOI

10.1016/j.cell.2025.05.013

Scopus ID

2-s2.0-105007602567 (requires institutional sign-in at Scopus site)   17 Citations

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.

Author List

Stevens J, Culberson E, Kinder J, Ramiriqui A, Gray J, Bonfield M, Shao TY, Al Gharaibeh F, Peterson L, Steinmeyer S, Eshleman EM, Negi S, Zacharias W, Pryhuber G, Paul O, Sengupta S, Alenghat T, Way SS, Deshmukh H

Author

Emily M. Eshleman PhD Assistant Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
CD8-Positive T-Lymphocytes
Dysbiosis
Female
Gastrointestinal Microbiome
Hepatocyte Nuclear Factor 1-alpha
Humans
Infant, Newborn
Influenza, Human
Inosine
Lung
Male
Mice
Mice, Inbred C57BL
Microbiota
Orthomyxoviridae Infections