Dictionary of immune responses to 86 cytokines in vivoat single-cell resolution

Abstract

Abstract Cytokines mediate cell-cell communication in the immune system and represent important therapeutic targets. A myriad of studies have underscored their central role in immune function, yet we lack a global view of the cellular responses of each immune cell type to each cytokine. To address this gap we created the Immune Dictionary – a compendium of single-cell transcriptomic profiles of over 20 cell types in response to each of 86 cytokines in murine lymph nodes in vivo, representing over 1,500 cytokine-cell type combinations. A cytokine-centric view of the dictionary revealed that most cytokines induced highly cell type-specific responses. For example, the inflammatory cytokine IL-1β induced distinct gene programs in almost every cell type. A cell type-centric view of the dictionary identified multiple cytokine-driven cellular polarization states in each immune cell type, including previously uncharacterized states such as an IL-18-induced polyfunctional NK cell state. Based on the dictionary, we developed companion software, Immune Response Enrichment Analysis (IREA), for assessing cytokine activities and immune cell polarization from gene expression data, and applied it to reveal cytokine networks in tumors following immune checkpoint blockade therapy. Our dictionary generates new hypotheses for cytokine functions, illuminates pleiotropic effects of cytokines, expands our knowledge of activation states of each immune cell type, and provides a framework to deduce the roles of specific cytokines and cell-cell communication networks in any immune response. This work was supported by the NIH Grant RM1HG006193 and an Adelson Medical Research Foundation Grant to N.H. This work was also supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Doctoral Fellowship, Whitaker Health Sciences Fund Fellowship, and Wellington and Irene Loh Fund Fellowship to A.C., and NCI Research Specialist Award (R50CA251956) to S.L.