Longitudinal multi-omic immune profiling reveals age-related immune cell dynamics in healthy adults 4083

Journal of Immunology 2025

Qiuyu Gong, M. Sharma, Emma L. Kuan, Marla C. Glass, Aishwarya Chander, Mansi Singh, Lucas T. Graybuck, Z. Thomson et al.

Abstract

The generation and maintenance of effective immunity is a dynamic and continuous process impacted by age. As people age, their immune systems become more susceptible to infections and respond less effectively to vaccines, yet the precise biological shifts driving these changes are not fully understood. To address this, we used multi-omic profiling (scRNA-seq, proteomics, flow cytometry) on over 300 adults, including 96 people tracked for two years with annual flu vaccination, generating >16 million PBMC profiles across 71 immune cell subsets in our Human Immune Health Atlas. This effort identified unique immune cell compositions and transcriptional states in homeostasis, after vaccination, and with aging. We find that T cells earlier in differentiation accumulate distinct age-related transcriptional changes more than other immune cells, independent from systemic inflammation and chronic perturbation. Moreover, impaired memory B cell responses to vaccination, including antibody isotype and neutralization function, are linked to gradual GATA3/Th2 polarization in multiple T cell subsets in older adults, revealing new features of immune dysregulation with healthy aging. Our study uncovers key age-driven shifts in immune cell states, identifying potential drivers of immune dysregulation as targets to augment functional immunity across age.

Research was supported by the Allen Institute, Benaroya Research Institute and by National Institute on Aging award K01AG068373 (C.E.G.)

Lymphocyte Differentiation and Peripheral Maintenance (LYM)

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