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Epigenomics of human CD8 T cell differentiation and aging

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Science Immunology  17 Feb 2017:
Vol. 2, Issue 8, eaag0192
DOI: 10.1126/sciimmunol.aag0192

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Defining the tree rings of T cells

T cell function declines with age. What does T cell aging look like at the molecular level? By generating genome-wide maps of chromatin accessibility in CD8 T cells from young and elderly individuals, Moskowitz et al. have furthered our understanding of transcriptional programs that regulate T cell differentiation and aging. They report that in naïve CD8 T cells in the elderly, promoters that recruit nuclear respiratory factor 1 (NRF1), a transcription factor that controls expression of mitochondrial proteins, are less accessible and propose that loss of NRF1 binding contributes to lower metabolic activity of aged T cells. The transcriptional circuits uncovered here set the stage for the designing rationales to modulate T cell function in the elderly.

Abstract

The efficacy of the adaptive immune response declines markedly with age, but the cell-intrinsic mechanisms driving immune aging in humans remain poorly understood. Immune aging is characterized by a loss of self-renewing naïve cells and the accumulation of differentiated but dysfunctional cells within the CD8 T cell compartment. Using the assay for transposase-accessible chromatin using sequencing, we inferred that the transcription factor binding activities correlated with naïve and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA sequencing, we identified transcription networks associated with CD8 T cell differentiation, with prominent roles implicated for BATF, ETS1, Eomes, and Sp1. Extending our analysis to aged humans, we found that the differences between the memory and naïve CD8 T cell subsets were largely preserved across age but that naïve and central memory cells from older individuals exhibited a shift toward more differentiated patterns of chromatin openness. In addition, aged naïve cells displayed a loss in chromatin accessibility at gene promoters, largely associated with a decrease in nuclear respiratory factor 1 (NRF1) binding. This shift was implicated in a marked drop-off in the ability of the aged naïve cells to transcribe respiratory chain genes, which may explain the reduced capacity of oxidative phosphorylation in older naïve cells. Our findings identify BATF- and NRF1-driven gene regulation as potential targets for delaying CD8 T cell aging and restoring function.

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