Interferon-γ（IFNγ）是细胞免疫反应的重要介质，但高水平的这种细胞因子与免疫病理学有关。IFNγ通过四个正电荷的C末端氨基酸（KRKR）和细胞外基质（ECM）结合到其受体（IFNγR）和ECM结合域（EBD）上。IFNγ在进化过程中变异性较大，但EBD高度保守，暗示其关键功能。我们展示了IFNγ不含EBD（IFNγΔKRKR）不与ECM结合，仍能与IFNγR结合并保持生物活性。IFNγΔKRKR在肿瘤中的过表达减少了局部的ECM结合，增加了系统水平并引起了病态行为、体重下降和毒性。为了分析EBD在感染过程中的功能，我们使用CRISPR-Cas9通过IFNγΔKRKR小鼠缺失EBD。感染淋巴细胞性脑膜炎病毒结果IFNγΔKRKR水平更高，病态行为增强，体重下降和致命毒性增加。我们得出结论：IFNγ的局部保留是在长时间免疫刺激期间保护有机体免受全身毒性的关键机制。©2023年，作者.

Interferon-γ (IFNγ) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNγ binds to its receptor (IFNγR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFNγ is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFNγ lacking the EBD (IFNγΔKRKR) does not bind to ECM but still binds to the IFNγR and retains bioactivity. Overexpression of IFNγΔKRKR in tumors reduced local ECM binding, increased systemic levels and induced sickness behavior, weight loss and toxicity. To analyze the function of the EBD during infection, we generated IFNγΔKRKR mice lacking the EBD by using CRISPR-Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNγΔKRKR levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFNγ is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation.© 2023. The Author(s).