tetano
Editor, Senior Moderator
Cell Rep
. 2026 Sep 3;45(9):117943.
doi: 10.1016/j.celrep.2026.117943. Online ahead of print.
Chen Lyu 1 , Jiuyang Xu 2 , Yulin Zhang 2 , Fei Zhu 3 , Di He 4 , Weiwei Ge 5 , Congcong Shang 6 , Qi Wang 7 , Wenting Zuo 1 , Yingying Yuan 8 , Yawen Ni 9 , Yitian Xu 1 , Ziyao Li 9 , Yuxian Mu 1 , Rongling Zhang 1 , Bin Cao 10
Affiliations
Metabolic alterations are increasingly recognized during influenza virus infection, but how local lactate accumulation shapes antiviral immunity remains poorly characterized. By integrating time-series targeted energy metabolomics, single-cell RNA sequencing, flow cytometry, and functional perturbation, we show that influenza virus infection preferentially increases lactate within the lung microenvironment, where it restrains pulmonary CD8+ T cell response. Mechanistically, extracellular lactate enters dendritic cells through monocarboxylate transporter (MCT)-dependent transport and induces a tolerogenic-like state marked by impaired maturation, reduced costimulation, and diminished CD8+ T cell-priming capacity. Direct experimental evidence identifies H3K18la as a prominent lactate-responsive histone lactylation mark, while multi-omics integration links it to enhancer accessibility and NRF2 pathway activation. Functional studies further show that NRF2 promotes dendritic cell suppression by reinforcing tolerogenic programs and limiting mtROS-dependent XBP1 splicing. Together, these findings reveal a lactate-driven histone lactylation-NRF2 pathway that modulates antiviral immunity during influenza infection.
Keywords: CD8(+) T cells; CP: immunology; dendritic cells; histone lactylation; influenza virus; lactate.
. 2026 Sep 3;45(9):117943.
doi: 10.1016/j.celrep.2026.117943. Online ahead of print.
Local lactate-driven H3K18 lactylation impairs anti-influenza immunity through NRF2-dependent dendritic cell dysfunction
Chen Lyu 1 , Jiuyang Xu 2 , Yulin Zhang 2 , Fei Zhu 3 , Di He 4 , Weiwei Ge 5 , Congcong Shang 6 , Qi Wang 7 , Wenting Zuo 1 , Yingying Yuan 8 , Yawen Ni 9 , Yitian Xu 1 , Ziyao Li 9 , Yuxian Mu 1 , Rongling Zhang 1 , Bin Cao 10
Affiliations
- PMID: 42690934
- DOI: 10.1016/j.celrep.2026.117943
Abstract
Metabolic alterations are increasingly recognized during influenza virus infection, but how local lactate accumulation shapes antiviral immunity remains poorly characterized. By integrating time-series targeted energy metabolomics, single-cell RNA sequencing, flow cytometry, and functional perturbation, we show that influenza virus infection preferentially increases lactate within the lung microenvironment, where it restrains pulmonary CD8+ T cell response. Mechanistically, extracellular lactate enters dendritic cells through monocarboxylate transporter (MCT)-dependent transport and induces a tolerogenic-like state marked by impaired maturation, reduced costimulation, and diminished CD8+ T cell-priming capacity. Direct experimental evidence identifies H3K18la as a prominent lactate-responsive histone lactylation mark, while multi-omics integration links it to enhancer accessibility and NRF2 pathway activation. Functional studies further show that NRF2 promotes dendritic cell suppression by reinforcing tolerogenic programs and limiting mtROS-dependent XBP1 splicing. Together, these findings reveal a lactate-driven histone lactylation-NRF2 pathway that modulates antiviral immunity during influenza infection.
Keywords: CD8(+) T cells; CP: immunology; dendritic cells; histone lactylation; influenza virus; lactate.