Deep longitudinal immune profiling reveals reprogramming of memory T cells that links to B cell dysregulation with age. Deep longitudinal immune profiling reveals reprogramming of memory T cells that links to B cell dysregulation with age

Immune aging is a dynamic process shaped by time and external perturbation. Here, we sought to untangle the complexity of the healthy human immunity across age using deep molecular profiling. Applying our new Healthy Immune Cell Atlas, we profiled the transcriptional dynamics of peripheral immune cells in a longitudinal cohort of ~100 healthy young and older adults followed over 2 years, both under homeostasis and perturbation induced by vaccination, building a scRNA-seq dataset of more than 13.5 million PBMCs. From these data, we revealed that T cells exhibit substantially more age-related changes in transcription at homeostasis than other immune cell subsets, which persist both over time and across age and are distinct from those associated with biological sex or CMV infection status. B cells, which demonstrated few age-related differences at homeostasis, had numerous and persistent changes in vaccine-induced responses with age linked to an age- and GATA3-related transcriptional skewing in the central memory CD4 T cell compartment of older adults. Our study collectively highlights that gradual, age-related alterations in the homeostatic transcriptional networks in immune cells leads to shifts in the landscape of immune responsiveness as we age. This rich resource is further provided with data exploration tools at https://explore.allenimmunology.org/. Overall design: The SoundLife cohort comprised of healthy young adults aged 25–35 years old and older adults aged 55–65 years old were recruited from the greater Seattle, WA area. Longitudinal visits were collected from these subjects prior to (Day 0) and following seasonal influenza vaccination (Day 7, Day 90) for two years. An additional Immune Variation series was collected over the course of 3 months (Day 0, 7, 90) and served as a baseline comparison of no vaccination/perturbation. A single stand-alone blood draw was also collected from these participants over the course of the two year study. Blood was drawn and PBMCs were isolated. PBMCs were assayed for flow cytometry and 10x 3' scRNA-seq (v3.1). *************************************************************** Submitter states that missing raw data are being made available for controlled access in dbGaP. ***************************************************************