Ge Hongchi, Guo Nan, Liu Yufei, Lang Bin, Yin Xiaowan, Yu Xiaowen, Zhang Zining, Fu Yajing, Ding Haibo, Hu Qinghai, Han Xiaoxu, Geng Wenqing, Shang Hong, Jiang Yongjun
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, NHC Key Laboratory of AIDS Prevention and Treatment, National Clinical Research Center for Laboratory Medicine, The First Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China.
mBio. 2025 Jun 11;16(6):e0023025. doi: 10.1128/mbio.00230-25. Epub 2025 Apr 29.
Natural killer (NK) cells are integral to the innate immune system and crucial for antiviral defense. NK cell activation and functional state are suppressed by inhibitory receptors. Lymphocyte activation gene 3 (LAG3) is an important inhibitory receptor, but the associated signaling pathways that regulate lymphocyte function remain to be elucidated. In addition, the effect of LAG3 on NK cell function during HIV infection and its specific mechanisms are unclear. In this study, we observed that LAG3 expression by NK cells is elevated in HIV-infected individuals and inversely correlated with CD4/CD8 ratio and CD4 T cell count. LAG3+ NK cells produce lower levels of interferon-gamma (IFN-γ), but LAG3-Fc protein significantly enhances NK cell function. The activation of LAG3 significantly inhibits IFN-γ production and Ki67 expression by NK cells. Our transcriptome sequencing and data show for the first time that LAG3 not only regulates the transcription of MYC and several glycolysis-related enzyme genes via the PI3K/AKT/mTOR signaling pathway to inhibit glycolysis in NK cells but also suppresses the STAT1/IFNG pathway by upregulating PSAT1 expression, thus limiting IFN-γ production by NK cells via these two different pathways. Overall, these results provide new insights and identify potential targets for immunotherapy of HIV infection.
We demonstrate that lymphocyte activation gene 3 (LAG3) expression is upregulated on natural killer (NK) cells during HIV infection. LAG3 inhibits glycolysis in NK cells and also upregulates PSAT1 expression to suppress activation of the STAT1/IFNG pathway, thus restricting interferon-gamma production by NK cells. These results provide new clues to study the effects of LAG3 on the metabolism and functional exhaustion of NK cells and offer a potential target for the treatment of HIV.
自然杀伤（NK）细胞是先天免疫系统的重要组成部分，对抗病毒防御至关重要。NK细胞的激活和功能状态受到抑制性受体的抑制。淋巴细胞激活基因3（LAG3）是一种重要的抑制性受体，但调节淋巴细胞功能的相关信号通路仍有待阐明。此外，LAG3在HIV感染期间对NK细胞功能的影响及其具体机制尚不清楚。在本研究中，我们观察到HIV感染个体中NK细胞的LAG3表达升高，且与CD4/CD8比值和CD4 T细胞计数呈负相关。LAG3+NK细胞产生较低水平的干扰素-γ（IFN-γ），但LAG3-Fc蛋白显著增强NK细胞功能。LAG3的激活显著抑制NK细胞产生IFN-γ和Ki67表达。我们的转录组测序和数据首次表明，LAG3不仅通过PI3K/AKT/mTOR信号通路调节MYC和几个糖酵解相关酶基因的转录，以抑制NK细胞中的糖酵解，还通过上调PSAT1表达抑制STAT1/IFNG通路，从而通过这两种不同途径限制NK细胞产生IFN-γ。总体而言，这些结果为HIV感染的免疫治疗提供了新见解并确定了潜在靶点。
我们证明，在HIV感染期间，自然杀伤（NK）细胞上淋巴细胞激活基因3（LAG3）的表达上调。LAG3抑制NK细胞中的糖酵解，并上调PSAT1表达以抑制STAT1/IFNG通路的激活,从而限制NK细胞产生干扰素-γ。这些结果为研究LAG3对NK细胞代谢和功能耗竭的影响提供了新线索，并为HIV治疗提供了潜在靶点。
