Center for Cancer Cell Biology, Immunology and Infection, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL.
Discipline of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL.
J Immunol. 2021 May 1;206(9):2170-2183. doi: 10.4049/jimmunol.2001459. Epub 2021 Apr 16.
The transcriptional and epigenetic regulation of CD8 T cell differentiation is critical for balancing pathogen eradication and long-term immunity by effector and memory CTLs, respectively. In this study, we demonstrate that the lysine demethylase 6b (Kdm6b) is essential for the proper generation and function of effector CD8 T cells during acute infection and tumor eradication. We found that cells lacking Kdm6b (by either T cell-specific knockout mice or knockdown using short hairpin RNA strategies) show an enhanced generation of memory precursor and early effector cells upon acute viral infection in a cell-intrinsic manner. We also demonstrate that Kdm6b is indispensable for proper effector functions and tumor protection, and that memory CD8 T cells lacking Kdm6b displayed a defective recall response. Mechanistically, we identified that Kdm6b, through induction of chromatin accessibility in key effector-associated gene loci, allows for the proper generation of effector CTLs. Our results pinpoint the essential function of Kdm6b in allowing chromatin accessibility in effector-associated genes, and identify Kdm6b as a potential target for therapeutics in diseases with dysregulated effector responses.
CD8 T 细胞分化的转录和表观遗传调控对于平衡效应器和记忆 CTL 分别清除病原体和长期免疫至关重要。在这项研究中，我们证明了赖氨酸去甲基酶 6b（Kdm6b）对于急性感染和肿瘤清除过程中效应 CD8 T 细胞的正常产生和功能是必需的。我们发现，在急性病毒感染中，缺乏 Kdm6b 的细胞（通过 T 细胞特异性敲除小鼠或短发夹 RNA 策略的敲低）以细胞内在的方式表现出记忆前体和早期效应细胞的增强产生。我们还证明了 Kdm6b 对于适当的效应功能和肿瘤保护是不可或缺的，并且缺乏 Kdm6b 的记忆 CD8 T 细胞表现出缺陷的回忆反应。在机制上，我们确定 Kdm6b 通过诱导关键效应相关基因座中的染色质可及性，允许效应 CTL 的正常产生。我们的结果指出了 Kdm6b 在允许效应相关基因染色质可及性方面的重要功能，并确定 Kdm6b 作为治疗失调效应反应疾病的潜在靶点。
