Epigenomics of human CD8 T cell differentiation and aging

Abstract

The efficacy of the adaptive immune response declines dramatically 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 ATAC-seq, we inferred the transcription factor binding activities correlated with naive and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA-seq, 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 naive subsets were largely preserved across age, but that naive and central memory cells from older individuals exhibited a shift toward more differentiated patterns of chromatin openness. Additionally, aged naive cells displayed a loss in chromatin accessibility at gene promoters, largely associated with a decrease in NRF1 binding. This shift was implicated in a marked drop-off in the ability of the aged naive 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.

Successful and Maladaptive T Cell Aging

“…Changes in CD8 + T cell transcriptomes are largely due to increased frequencies of effector CD8 + T cells (Cao et al, 2010). A separate analysis of CD28 + and CD28 − CD8 + T cells in young and old individuals were consistent with the model that old CD28 + CD8 + T cells were more differentiated (Lazuardi et al, 2009) as also suggested by the epigenetic studies of CD8 + T cell subsets (Moskowitz et al, 2017). Because a major feature of T cell aging appears to be the initiation of differentiation steps, the analysis of individual T cell subsets in functional studies is important.…”

“…Repression of PGC1α, an important cofactor of NRF1 activity, is an early event in T cell exhaustion, indicating a mechanistic overlap between T cell aging and exhaustion (Bengsch et al, 2016). However, CD8 + CD45RO + CCR7 − effector memory T cells from older individuals show only few differences in terms of chromatin accessibility compared to young effector memory T cells, and they lack the epigenetic signatures of exhausted T cells (Moskowitz et al, 2017; Sen et al, 2016). This observation suggests that T cell aging mainly affects naive and central memory CD8 + T cells, possible employing pathways similar to exhaustion.…”

“…The recent invention of the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) has facilitated the ability to interrogate the epigenome using a small number of cells. In a recent study, genome-wide maps of chromatin accessibility were generated for purified CD8 + T cell subsets from age-segregated human individuals and compared to transcriptome analysis (Moskowitz et al, 2017). Changes throughout differentiation were defined by comparing naive, effector, and central memory T cells; these analyses were complemented by examining the impact of age on the chromatin landscapes and identifying the associated regulatory programs.…”

“…However, some of the pathways that induce T cell exhaustion may be shared with those that are involved in T cell aging and senescence. Epigenetic studies of human naive and central memory CD8 + T cells revealed an age-associated loss of chromatin accessibility at key promoters, in particular at NRF1 binding sites (Moskowitz et al, 2017). The loss in NRF1 binding appears to account for the reduced expression of mitochondrial respiratory chain genes and defective oxidative phosphorylation that could result in poor T cell survival (Figure 2), reminiscent of the mitochondrial dysfunction-associated senescence identified by Wiley et al (2016) in proliferating cells with mitochondrial defects.…”

Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells

“…Contrary to earlier predictions, the size and diversity of the human CD4 + T cell repertoire in older individuals is sufficient to respond to a diverse set of antigenic peptides (Qi et al, 2014). The CD8 + T cell compartment is more affected by age, both in size and composition as well as in function and chromatin structure (Briceño et al, 2016; Czesnikiewicz-Guzik et al, 2008; Moskowitz et al, 2017; Nikolich-Zugich et al, 2012). Defects in T cell activation because of reduced dendritic cell function or T cell receptor (TCR) signaling have been described (Li et al, 2012; Montgomery and Shaw, 2015) and may be overcome by adjuvanted vaccines or increasing the antigen dose (DiazGranados et al, 2014).…”