Immune System Organization is Encoded in Transcription

Abstract

Immune responses are often interpreted as cell type-specific transcriptional programs driven by external stimuli, with variation typically analyzed within each cell type. Here we show that immune organization is reflected in coordinated changes in gene expression across cell types within individuals, forming a shared low-dimensional state space. Using single-cell transcriptomes from a large longitudinal cohort, we find that thousands of genes vary coherently relative to subtype-specific reference profiles, defining this low-dimensional structure. Across individuals and over time, these deviations organize into a small number of recurring, temporally stratified patterns of transcriptional change. Dominant patterns reflect temporal dynamics shared across individuals, whereas others encode stable individual-specific transcriptional configurations. This donor-level coordination is observed across tissues, is reflected in cell surface protein expression and is captured in matched serum proteomics. Importantly, responses to in vitro cytokine stimulation are coordinated across cell types within donors, demonstrating that donor-level transcriptional organization is preserved under perturbation. Together, these results show that donor-level organization is evident in both transcriptional state and responses to perturbation, manifesting across cell types, tissues and time.