Misel-Wuchter Kara M, Thurman Andrew L, Johnson Jordan T, Teghanemt Athmane, Gautam Neelam, Pezzulo Alejandro A, Bermick Jennifer R, Butler Noah S, Issuree Priya D
Inflammation Program, University of Iowa, Iowa City, IA, USA.
Molecular Medicine Graduate Program, University of Iowa, Iowa City, IA, USA.
EMBO Rep. 2025 Apr 2. doi: 10.1038/s44319-025-00439-z.
In response to infections, naive CD8 T cells give rise to effector and memory T cells. However, eliciting long-lived memory CD8 T cells remains a challenge for many infections. DNA demethylation of cytosines within CpG dinucleotides by Tet enzymes is a key epigenetic mechanism that regulates short- and long-term transcriptional programs in cells. Currently, their roles in modulating CD8 T-cell effector and memory differentiation are unclear. Here, we report that developing CD8 T cells lacking Tet1/3 preferentially differentiate into short-lived effector and effector memory cells following acute infection. Using genome-wide analyses, mice in which Tet1/3 were ablated during T-cell development and mature CD8 T cells, respectively, we show that Tet1/3 regulates these cell fates by licensing the chromatin landscape of genes downstream of T-cell receptor activation during thymic T-cell maturation. However, in mature CD8 T cells, Tet1/3 are dispensable for effector and memory cell fates. These findings unveil context-specific roles of DNA demethylation, which are essential for defining pathways that contribute to CD8 memory T-cell generation in response to infections.
针对感染，初始CD8 T细胞会分化为效应T细胞和记忆T细胞。然而，对于许多感染而言，诱导产生长寿的记忆CD8 T细胞仍然是一项挑战。Tet酶介导的CpG二核苷酸内胞嘧啶的DNA去甲基化是一种关键的表观遗传机制，可调节细胞中的短期和长期转录程序。目前，它们在调节CD8 T细胞效应器和记忆分化中的作用尚不清楚。在此，我们报告，缺乏Tet1/3的发育中的CD8 T细胞在急性感染后优先分化为短命效应细胞和效应记忆细胞。通过全基因组分析，分别在T细胞发育过程中敲除Tet1/3的小鼠以及成熟CD8 T细胞，我们发现Tet1/3通过在胸腺T细胞成熟过程中许可T细胞受体激活下游基因的染色质景观来调节这些细胞命运。然而，在成熟CD8 T细胞中，Tet1/3对于效应细胞和记忆细胞命运是可有可无的。这些发现揭示了DNA去甲基化在特定背景下的作用，这对于确定在感染后有助于产生CD8记忆T细胞的途径至关重要。
