Weyand, C. M. | bioRxiv Science

bioRxiv2021

The STAT5-IRF4-BATF pathway drives heightened epigenetic remodeling in naïve CD4+ T cell responses of older adults

T cell aging is a complex process combining the emergence of cellular defects with activation of adaptive mechanisms. Generation of T cell memory is impaired, while a low-inflammatory state is induced, in part due to effector T cells. To determine whether age-associated changes in T cell fate decisions occur early after T cell activation, we profiled the longitudinal transcriptional and epigenetic landscape induced by TCR stimulation comparing naive CD4+ T cells from young and older adults. In spite of attenuated TCR signaling, activation-induced remodeling of the epigenome increased with age, culminating in heightened BATF and BLIMP1 activity. Single cell studies, integrating ATAC-seq and RNA-seq data, identified increases in dysfunctional and in effector T cells and a decrease in BACH2-expressing memory cell precursors. STAT5 activation, in part due to a decline in HELIOS and aberrant IL-2 receptor expression, accounted for the induction of transcription factor networks favoring effector cell differentiation.

immunology↗

bioRxiv2021

Influence of age on functional memory T cell diversity

Memory T cells exhibit considerable diversity that determines their ability to be protective and their durability. Here, we examined whether changes in T cell heterogeneity contribute to the age-associated failure of immune memory. By screening for age-dependent T cell surface markers, we have identified CD4 and CD8 memory T cell subsets that are unrelated to previously defined subsets of central and effector memory cells. Memory T cells expressing the ecto-5-nucleotidase CD73 constitute a functionally distinct subset of memory T cells that declines with age. They exhibit many features favorable for immune protection, including longevity and polyfunctionality. They have a low turnover, but are poised to display effector functions and to develop into cells resembling tissue-resident memory T cells (TRM). Upstream regulators of differential chromatin accessibility and transcriptomes include transcription factors that are characteristic for conferring these superior memory features as well as facilitating CD73 expression. CD73 is not just a surrogate marker of these regulatory networks but is directly involved in T cell survival and TRM differentiation Interventions preventing the decline of this T cell subset or increasing CD73 expression have the potential to improve immune memory in older adults.

immunology↗