An atlas of gene regulatory networks for T memory cells in youth and old age.

Aging profoundly affects immune system function, rendering the elderly more susceptible to pathogens, cancers and chronic inflammation. We previously identified a population of IL-10- producing, T follicular helper-like cells (" Tfh10 "), linked to suppressed vaccine responses in aged mice. Here, we use the power of single-cell ( sc )genomics and genome-scale modeling to characterize Tfh10 - and the full CD4 + memory T cell ( CD4 + TM ) compartment - in young and old mice. Unprecedented scRNA-seq coverage of the CD4 + TM compartment and parallel chromatin accessibility measurements (scATAC-seq) enabled identification of 13 CD4 + TM populations, which we validated as a reference through comprehensive cross-comparison to aging cell atlases and scRNA-seq studies reporting Tfh10 in other contexts. Beyond robust characterization of age- and cell-type-dependent transcriptional landscapes, we used integrative computational modeling to predict the underlying regulatory mechanisms: We inferred gene regulatory networks ( GRNs ) that describe transcription-factor control of gene expression in each T-cell population and how these circuits change with age. Furthermore, we integrated our data with prior, pan-cell scRNA- seq studies to identify intercellular-signaling networks driving age-dependent changes in CD4 + TM. Our atlas of finely resolved CD4 + TM subsets, GRNs and cell-cell communication networks is a critical resource for analysis of biologic processes operative in memory T cells in youth and old age. The resource presents new opportunities to manipulate regulatory circuits in CD4 + TM, which, long-term, could improve immune responses in the elderly.