Bhatt Brinda, Kumar Kunal, Shi Huidong, Ganesan Dhasarathan, Anazodo Francis, Rathakrishnan Aravind, Zhu Huabin, Wanna Andrew, Jiang Chen, Jayavelu Tamilselvan, Lokeshwar Vinata Bal, Pacholczyk Rafal, Munn David H, Sheridan Brian S, Moskophidis Demetrius, Li Honglin, Singh Nagendra
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States.
Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States.
J Immunol. 2025 Feb 24;214(3):446-59. doi: 10.1093/jimmun/vkae042.
In naïve mice, a fraction of CD8 T cells displaying high affinity for self-MHC peptide complexes develop into virtual memory T (TVM) cells. Due to self-reactivity, TVM cells are exposed to persistent antigenic stimulation, a condition known to induce T cell exhaustion. However, TVM cells do not exhibit characteristics similar to exhausted CD8 T (TEX) cells. Here, we tested the role of the UFL1, E3 ligase of the ufmylation pathway in TVM cells. We show that UFL1 prevents the acquisition of epigenetic, transcriptional, and phenotypic changes in TVM cells that are similar to TEX cells and thus promote their survival and function. UFL1-deficient TVM cells failed to protect mice against Listeria infection. Epigenetic analysis showed higher BATF activity in UFL1-deficient TVM cells. Deletion of BATF and not PD1 decreased inhibitory molecules expression and restored the survival and function of UFL1-deficient TVM cells. Our findings demonstrate a key role of UFL1 in inhibiting the exhaustion of TVM cells and promoting their survival and function.
在未经致敏的小鼠中，一部分对自身MHC肽复合物具有高亲和力的CD8 T细胞会发育为虚拟记忆T（TVM）细胞。由于自身反应性，TVM细胞会受到持续的抗原刺激，这种情况已知会诱导T细胞耗竭。然而，TVM细胞并不表现出与耗竭的CD8 T（TEX）细胞相似的特征。在此，我们测试了泛素样修饰因子1（UFL1）（泛素样修饰途径的E3连接酶）在TVM细胞中的作用。我们发现，UFL1可防止TVM细胞发生与TEX细胞相似的表观遗传、转录和表型变化，从而促进其存活和功能。缺乏UFL1的TVM细胞无法保护小鼠免受李斯特菌感染。表观遗传分析显示，缺乏UFL1的TVM细胞中BATF活性更高。敲除BATF而非PD1可降低抑制性分子的表达，并恢复缺乏UFL1的TVM细胞的存活和功能。我们的研究结果证明了UFL1在抑制TVM细胞耗竭并促进其存活和功能方面的关键作用。
