Frontiers in immunology · 2026
Frequency-selective thymic programming by early-life cold stress requires interferon regulatory factor 5.
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Wang Shengnan, Li Liyuan, Li Haokun, Qu Kuo, Wang Liying, Sun Wei
Аннотация
BACKGROUND: Early-life environmental stressors can program immune development, but how the frequency of cold stress shapes thymic programming remains unknown.
METHODS: Developmentally matched (day 4, poikilothermic, yolk sac or milk dependent) zebrafish larvae and neonatal mice were exposed to two or four cycles of cold stress (termed 2× or 4× stress). Thymic development (zebrafish) and thymic T cell subsets (mice) were assessed, followed by influenza A virus (IAV) challenge in mice. Mechanisms were explored by RT-qPCR, western/dot blotting, and irf4/5 transgenic or irf5 knockout zebrafish.
RESULTS: In Tg(rag2:DsRed) zebrafish larvae, 2× stress increased the percentage of larvae exhibiting a DsRed+ thymus, without significantly altering overall fluorescence area and MFI of the thymus, whereas 4× stress markedly reduced both of the latter parameters. These opposite phenotypic effects correlated with divergent expression patterns of lepb, lepr, irf4/5, and stat3. In neonatal mice, 2× stress enhanced thymic CD3 expression on CD4+CD8+(DP) and CD4+ cells and improved acute survival following IAV infection, whereas 4× stress reduced DP proportion and CD3 expression across multiple subsets, increased CD4+ cells, and offered no acute protection against IAV infection, yet unexpectedly enhanced long-term survival when infected as adults. 2× and 4× stress induced divergent dynamics of leptin, IRF4/5 and inflammatory factors. Transgenic overexpression of irf5, but not irf4, reprogrammed the frequency-selective cold stress response in larvae, irf5 knockout subsequently abrogated these effects on thymic development and altered baseline expression of leptin signaling-related genes.
CONCLUSION: Early-life cold stress programs thymic immunity in a frequency-selective manner. Zebrafish genetics establish a causal requirement for IRF5, while mouse data show correlative changes in leptin signaling and IRF4/5. These findings highlight stress frequency as a key determinant of early-life immune programming and suggest potential windows for precise immunomodulation.
METHODS: Developmentally matched (day 4, poikilothermic, yolk sac or milk dependent) zebrafish larvae and neonatal mice were exposed to two or four cycles of cold stress (termed 2× or 4× stress). Thymic development (zebrafish) and thymic T cell subsets (mice) were assessed, followed by influenza A virus (IAV) challenge in mice. Mechanisms were explored by RT-qPCR, western/dot blotting, and irf4/5 transgenic or irf5 knockout zebrafish.
RESULTS: In Tg(rag2:DsRed) zebrafish larvae, 2× stress increased the percentage of larvae exhibiting a DsRed+ thymus, without significantly altering overall fluorescence area and MFI of the thymus, whereas 4× stress markedly reduced both of the latter parameters. These opposite phenotypic effects correlated with divergent expression patterns of lepb, lepr, irf4/5, and stat3. In neonatal mice, 2× stress enhanced thymic CD3 expression on CD4+CD8+(DP) and CD4+ cells and improved acute survival following IAV infection, whereas 4× stress reduced DP proportion and CD3 expression across multiple subsets, increased CD4+ cells, and offered no acute protection against IAV infection, yet unexpectedly enhanced long-term survival when infected as adults. 2× and 4× stress induced divergent dynamics of leptin, IRF4/5 and inflammatory factors. Transgenic overexpression of irf5, but not irf4, reprogrammed the frequency-selective cold stress response in larvae, irf5 knockout subsequently abrogated these effects on thymic development and altered baseline expression of leptin signaling-related genes.
CONCLUSION: Early-life cold stress programs thymic immunity in a frequency-selective manner. Zebrafish genetics establish a causal requirement for IRF5, while mouse data show correlative changes in leptin signaling and IRF4/5. These findings highlight stress frequency as a key determinant of early-life immune programming and suggest potential windows for precise immunomodulation.