AUTHOR=Kim Jaekwan , Nguyen Thomas , Cifello Jeffrey , Ahmad Raheel , Zhang Yongqing , Yang Qian , Lee Ji-Eun , Li Xiang , Kai Yan , De Supriyo , Peng Weiqun , Ge Kai , Weng Nan-ping 

TITLE=Lysine methyltransferase Kmt2d regulates naive CD8+ T cell activation-induced survival

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1095140

DOI=10.3389/fimmu.2022.1095140

ISSN=1664-3224

ABSTRACT=<p>Lysine specific methyltransferase 2D (Kmt2d) catalyzes the mono-methylation of histone 3 lysine 4 (H3K4me1) and plays a critical role in regulatory T cell generation <italic>via</italic> modulating Foxp3 gene expression. Here we report a role of Kmt2d in naïve CD8<sup>+</sup> T cell generation and survival. In the absence of <italic>Kmt2d</italic>, the number of CD8<sup>+</sup> T cells, particularly naïve CD8<sup>+</sup> T cells (CD62L<sup>hi</sup>/CD44<sup>lo</sup>), in spleen was greatly decreased and <italic>in vitro</italic> activation-related death significantly increased from <italic>Kmt2d</italic><sup>fl/fl</sup>CD4cre<sup>+</sup> (KO) compared to <italic>Kmt2d</italic><sup>fl/fl</sup>CD4cre<sup>-</sup> (WT) mice. Furthermore, analyses by ChIPseq, RNAseq, and scRNAseq showed reduced H3K4me1 levels in enhancers and reduced expression of apoptosis-related genes in activated naïve CD8<sup>+</sup> T cells in the absence of Kmt2d. Finally, we confirmed the activation-induced death of antigen-specific naïve CD8<sup>+</sup> T cells <italic>in vivo</italic> in Kmt2d KO mice upon challenge with <italic>Listeria monocytogenes</italic> infection. These findings reveal that Kmt2d regulates activation-induced naïve CD8<sup>+</sup> T cell survival <italic>via</italic> modulating H3K4me1 levels in enhancer regions of apoptosis and immune function-related genes.</p>