Mechanisms Of Age-related Changes in Transcriptional Regulation in lympphocytes

National Institute On Aging

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Abstract

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 via modulating Foxp3 gene expression. Here we report a role of Kmt2d in nave CD8+ T cell generation and survival. In the absence of Kmt2d, the number of CD8+ T cells, particularly nave CD8+ T cells (CD62Lhi/CD44lo), in spleen was greatly decreased and in vitro activation-related death significantly increased from Kmt2dfl/flCD4cre+ (KO) compared to Kmt2dfl/flCD4cre- (WT) mice. Furthermore, analyses by ChIPseq, RNAseq, and scRNAseq showed reduced H3K4me1 levels in enhancers and reduced expression of apoptosis-related genes in activated nave CD8+ T cells in the absence of Kmt2d. Finally, we confirmed the activation-induced death of antigen-specific nave CD8+ T cells in vivo in Kmt2d KO mice upon challenge with Listeria monocytogenes infection. These findings reveal that Kmt2d regulates activation-induced nave CD8+ T cell survival via modulating H3K4me1 levels in enhancer regions of apoptosis and immune function-related genes. The ability of T cells to undergo robust cell division in response to antigenic stimulation is essential for competent T cell function. However, this ability is reduced with aging, contributing to an increased susceptibility to infectious diseases, cancers, and other diseases among older adults. To better understand T cell aging, improved measurements of age-related cellular changes in T cells are necessary. The recent development of a machine-learning assisted transcriptome-based quantification of individual CD8+ T cell age represents a significant step forward in this regard. It reveals both prominent and subtle changes in gene expression and points to potential functional alterations of CD8+ T cells with aging. By capturing differences in the status of cell differentiation and history of cell divisions, this algorithm assigns different ages to CD8+ T cells, which enables researchers to better comprehend the impact of age on the functions of individual CD8+ T cells. We argue that single cell transcriptome-based age prediction in the immune system may have promising future applications.