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/. A cohort of healthy participants aged 40-89+ was recruited for this study in the greater Palo Alto, CA area. A subset of 235 donors was selected from a larger pool of 800+ donors to represent our confirmatory cohort. This sample subset comprises 136 female and 98 male donors spanning ages 40-89+. The ethnicities of the donors include 132 Caucasians, 49 Asians, 12 African Americans, 4 American Indians, 2 Pacific Islanders, and 35 others. The population distribution was selected to be representative of Palo Alto, CA. Blood was collected from all participants at a single time point and PBMCs were isolated. PBMCs were assayed using the 10x flex scRNA-seq chemistry.