Distinct Age-Related Epigenetic Signatures in CD4 and CD8 T Cells

TL;DR

This study finds that CD4 T cells are more resistant to aging than CD8 T cells due to differences in epigenetic changes.

Contribution

The paper identifies distinct age-related epigenetic signatures in CD4 and CD8 T cells that explain their differing resilience to aging.

Findings

CD8 T cells show stronger age-related differentiation signatures compared to CD4 T cells.

Old CD8 T cells have reduced chromatin accessibility for genes related to basic cell functions.

Lower YY1 and NRF1 expression may contribute to the epigenetic changes in CD8 T cells.

Abstract

Healthy immune aging is in part determined by how well the sizes of naïve T cell compartments are being maintained with advancing age. Throughout adult life, replenishment largely derives from homeostatic proliferation of existing naïve and memory T cell populations. However, while the subpopulation composition of CD4 T cells is relatively stable, the CD8 T cell compartment undergoes more drastic changes with loss of naïve CD8 T cells and accumulation of effector T cells, suggesting that CD4 T cells are more resilient to resist age-associated changes. To determine the epigenetic basis for these differences in behaviors, we compared chromatin accessibility maps of CD4 and CD8 T cell subsets from young and old individuals and related the results to the expressed transcriptome. The dominant age-associated signatures resembled hallmarks of differentiation, which were more pronounced for CD8 naïve and memory than the corresponding CD4 T cell subsets, indicating that CD8 T cells are less able to keep cellular quiescence upon homeostatic proliferation. In parallel, CD8 T cells from old adults, irrespective of their differentiation state, displayed greater reduced accessibility to genes of basic cell biological function, including genes encoding ribosomal proteins. One possible mechanism is the reduced expression of the transcription factors YY1 and NRF1. Our data suggest that chromatin accessibility signatures can be identified that distinguish CD4 and CD8 T cells from old adults and that may confer the higher resilience of CD4 T cells to aging.

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