tetano
Editor, Senior Moderator
Cell
. 2025 Jun 3:S0092-8674(25)00563-X.
doi: 10.1016/j.cell.2025.05.013. Online ahead of print. Microbiota-derived inosine programs protective CD8[SUP]+[/SUP] T cell responses against influenza in newborns
Joseph Stevens[SUP] 1 [/SUP], Erica Culberson[SUP] 1 [/SUP], Jeremy Kinder[SUP] 2 [/SUP], Alicia Ramiriqui[SUP] 3 [/SUP], Jerilyn Gray[SUP] 3 [/SUP], Madeline Bonfield[SUP] 4 [/SUP], Tzu-Yu Shao[SUP] 2 [/SUP], Faris Al Gharaibeh[SUP] 5 [/SUP], Laura Peterson[SUP] 5 [/SUP], Shelby Steinmeyer[SUP] 6 [/SUP], Emily M Eshleman[SUP] 7 [/SUP], Shikha Negi[SUP] 7 [/SUP], William Zacharias[SUP] 8 [/SUP], Gloria Pryhuber[SUP] 9 [/SUP], Oindrila Paul[SUP] 10 [/SUP], Shaon Sengupta[SUP] 10 [/SUP], Theresa Alenghat[SUP] 7 [/SUP], Sing Sing Way[SUP] 2 [/SUP], Hitesh Deshmukh[SUP] 11 [/SUP]
Affiliations
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[SUP]+[/SUP] 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[SUP]+[/SUP] 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[SUP]+[/SUP] 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.
. 2025 Jun 3:S0092-8674(25)00563-X.
doi: 10.1016/j.cell.2025.05.013. Online ahead of print. Microbiota-derived inosine programs protective CD8[SUP]+[/SUP] T cell responses against influenza in newborns
Joseph Stevens[SUP] 1 [/SUP], Erica Culberson[SUP] 1 [/SUP], Jeremy Kinder[SUP] 2 [/SUP], Alicia Ramiriqui[SUP] 3 [/SUP], Jerilyn Gray[SUP] 3 [/SUP], Madeline Bonfield[SUP] 4 [/SUP], Tzu-Yu Shao[SUP] 2 [/SUP], Faris Al Gharaibeh[SUP] 5 [/SUP], Laura Peterson[SUP] 5 [/SUP], Shelby Steinmeyer[SUP] 6 [/SUP], Emily M Eshleman[SUP] 7 [/SUP], Shikha Negi[SUP] 7 [/SUP], William Zacharias[SUP] 8 [/SUP], Gloria Pryhuber[SUP] 9 [/SUP], Oindrila Paul[SUP] 10 [/SUP], Shaon Sengupta[SUP] 10 [/SUP], Theresa Alenghat[SUP] 7 [/SUP], Sing Sing Way[SUP] 2 [/SUP], Hitesh Deshmukh[SUP] 11 [/SUP]
Affiliations
- PMID: 40494345
- DOI: 10.1016/j.cell.2025.05.013
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[SUP]+[/SUP] 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[SUP]+[/SUP] 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[SUP]+[/SUP] 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.