W154 - Transcriptional Dynamics in Peripheral Immune Cells Across Healthy Aging

Lynne Becker – Allen Institute for Immunology; Jane Buckner – Benaroya Research Institute; Thomas Bumol – Allen Institute for Immunology; Ernie Coffey – Allen Institute for Immunology; Matthew Dufort – Benaroya Research Institute; Jessica Garber – Allen Institute for Immunology; Palak Genge – Allen Institute for Immunology; Marla Glass – Allen Institute for Immunology; Ananda Goldrath – Allen Institute for Immunology; qiuyu Gong – Allen Institute for Immunology; Lucas Graybuck – Allen Institute for Immunology; veronica hernandez – Allen Institute for Immunology; Alex Heubeck – Allen Institute for Immunology; Alex Hu – Benaroya Research Institute; Emma Kuan – Allen Institute for Immunology; Kevin Lee – Allen Institute for Immunology; Xiao-jun Li – Allen Institute for Immunology; Paul Meijer – Allen Institute for Immunology; Regina Mettey – Allen Institute for Immunology; Tao Peng – Allen Institute for Immunology; Cole Phalen – Allen Institute for Immunology; Julian Reading – Allen Institute for Immunology; Charles Roll – Allen Institute for Immunology; Adam Savage – Allen Institute for Immunology; Mehul Sharma – Allen Institute for Immunology; Mansi Singh – Allen Institute for Immunology; Peter Skene – Allen Institute for Immunology; Megan smithmyer – Benaroya Research Institute; Cate Speake – Benaroya Research Institute; Tyanna Stuckey – Allen Institute for Immunology; Elliot Swanson – Allen Institute for Immunology; Zach Thomson – Allen Institute for Immunology; Troy Torgerson – Allen Institute for Immunology; Morgan Weiss – Allen Institute for Immunology

Abstract Text: Immune aging is a dynamic process driven by complex internal and external interactions. Here, we sought to untangle the complexity of the healthy human immune system across age using deep molecular profiling. We first built a peripheral immune cell reference characterizing more than 1.8 million peripheral blood mononuclear cells (PBMCs) across 108 healthy people (age range:11-65 years) using scRNAseq, identifying a total of 71 distinct cell subsets. We then applied this reference to study the transcriptional dynamics of immune cells in our longitudinal aging cohort of healthy young (n=47, 25-35yrs) and older (n=45, 55-65yrs) adults followed over the course of 2-3 years (final dataset ~20 million PBMCs). We observed that T cells exhibit substantially more age-related changes in transcription than other immune cell subsets, suggesting that they may reveal clues to understanding the molecular basis of immune age. Age-related transcriptional changes in T cell subsets were closely associated with T cell differentiation state (i.e., naïve T cells> central memory>>>effector memory) but were not uniformly associated with age-related compositional shifts, were distinct from CMV-related expression changes and were stably maintained over the course of more than one year. Moreover, an age-related accumulation of GZMK+ effector memory CD8 T cells was linked with increased GATA3 expression in the naïve compartment of older adults and with upstream STAT6 signaling – suggesting that gradual, age-related alterations of transcriptional networks in T cells may skew their differentiation trajectories and in turn, lead to shifts in the compositional landscape of immune cells as we age.