Distinct Age-Related Epigenetic Signatures in CD4 and 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.

The GSK3β-β-catenin-TCF1 pathway improves naive T cell activation in old adults by upregulating miR-181a

“…In previous studies, we have found YY1 to be an important regulator of pri-miR-181a/b1 transcription. YY1 expression in T cells declines with age, in particular in CD8 T cells where ageassociated losses in chromatin accessibility are enriched for YY1 binding motifs 34,35 . However, it is currently unknown how to target the defect in YY1 binding.…”

Reduced chromatin accessibility to CD4 T cell super-enhancers encompassing susceptibility loci of rheumatoid arthritis

“…ATAC-seq libraries were generated on naïve, CM and EM CD4 T cells following the standard protocol described previously. 21 , 22 Briefly, 50,000 sorted T cells were washed with cold PBS and RSB buffer (10mM Tris-HCl (pH 7.4), 10mM NaCl, 3mM MgCl 2 ) followed by washing with RSB buffer containing 0.1% NP-40 and 0.1% Tween 20. Cell pellets were resuspended in the transposase reaction mix (25μL 2 × TD buffer, 2.5μL transposase (Illumina) and 22.5μL nuclease-free water) and incubated at 37°C for 30 min.…”

“…Sequencing reads were processed and normalized as described before. 21 , 22 The samples were sequenced in 6 batches. To maintain stringency, an aggregate peak set was generated by including sites present in at least 3 or more samples followed by exclusion of sites with low read counts using the filterByExpr function across sample groups.…”

miR-181a-regulated pathways in T-cell differentiation and aging

“…YY1 has been implicated in many biological processes such as cell growth and development, where it functions as a transcriptional activator or repressor depending on the interaction with other cofactors [ 84 , 85 ]. Along with the age-related decline in YY1 expression, naïve CD8 T cells from the elderly show reduced chromatin accessibility to YY1 binding sites at gene promoters [ 86 , 87 ]. YY1 silencing had only minimal effects on the transcriptome of unstimulated naïve CD4 T cells beyond miR-181a expression [ 73 ].…”