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

Joseph Stevens¹, Erica Culberson¹, Jeremy Kinder², Alicia Ramiriqui³, Jerilyn Gray³, Madeline Bonfield⁴, Tzu-Yu Shao², Faris Al Gharaibeh⁵, Laura Peterson⁵, Shelby Steinmeyer⁶, Emily M Eshleman⁷, Shikha Negi⁷, William Zacharias⁸, Gloria Pryhuber⁹, Oindrila Paul¹⁰, Shaon Sengupta¹⁰, Theresa Alenghat⁷, Sing Sing Way², Hitesh Deshmukh¹¹

Affiliations

¹ 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.
² 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.
³ Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁴ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁵ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁶ Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA.
⁷ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁸ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁹ Department of Pediatrics, School of Medicine, University of Rochester, Rochester, NY, USA.
¹⁰ Division of Neonatology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: hitesh.deshmukh@cchmc.org.

PMID: 40494345
PMCID: PMC12335363 (available on 2026-06-09)
DOI: 10.1016/j.cell.2025.05.013

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

Joseph Stevens et al. Cell. 2025.

. 2025 Aug 7;188(16):4239-4256.e19.

doi: 10.1016/j.cell.2025.05.013. Epub 2025 Jun 9.

Authors

Affiliations

¹ 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.
² 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.
³ Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁴ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁵ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁶ Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA.
⁷ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁸ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁹ Department of Pediatrics, School of Medicine, University of Rochester, Rochester, NY, USA.
¹⁰ Division of Neonatology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: hitesh.deshmukh@cchmc.org.

PMID: 40494345
PMCID: PMC12335363 (available on 2026-06-09)
DOI: 10.1016/j.cell.2025.05.013

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.

Keywords: T cell responses; immunology; infants; influenza; inosine; microbiota.

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Conflict of interest statement

Declaration of interests J.S. and H.D. are named as co-inventors on a provisional patent application relating to this work entitled “Methods and compositions for enhancing CD8(+) T cell-mediated immune responses in neonates,” which was filed on 4/11/2025 under application number 62/787,417 with the United States Patent and Trademark Office.

Update of

Microbiota-derived inosine programs protective CD8⁺ T cell responses against influenza in newborns.
Stevens J, Culberson E, Kinder J, Ramiriqui A, Gray J, Bonfield M, Shao TY, Al Gharabieh F, Peterson L, Steinmeyer S, Zacharias W, Pryhuber G, Paul O, Sengupta S, Alenghat T, Way SS, Deshmukh H. Stevens J, et al. bioRxiv [Preprint]. 2024 Apr 13:2024.04.09.588427. doi: 10.1101/2024.04.09.588427. bioRxiv. 2024. Update in: Cell. 2025 Aug 7;188(16):4239-4256.e19. doi: 10.1016/j.cell.2025.05.013. PMID: 38645130 Free PMC article. Updated. Preprint.

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

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

Authors

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Conflict of interest statement

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