The Separable Organization of Immune Transcriptional Responses

Abstract

Immune function depends on coordinated responses across diverse cell types, yet the organizing principles underlying this coordination remain uncertain. Here we analyze single-cell data of peripheral blood mononuclear cells from 12 donors exposed in vitro to 90 cytokines and find that, for a given donor and perturbation, transcriptional responses in one cell type can be transformed into corresponding responses in another through mappings that depend only on the identities of the two cell types. These cross-cell-type mappings admit a separable organization in which each donor-perturbation pair is represented by a response state shared across cell types, while donor- and perturbation-independent cell-type-specific response rules specify how that state is expressed. We formalize this organization as a linear shared-state model that captures most of the reproducible transcriptional response variance. This separation between shared response state and cell-type-specific response rules generalizes to unseen donors and perturbations and extends to longitudinal variation in vivo. Thus, our results reveal an organizing principle of immune coordination, with distinct transcriptional responses across cell types representing cell-type-specific expressions of a shared donor-level response state.