Active eosinophils regulate host defense and immune responses in colitis


Alessandra Gurtner, Costanza Borrelli, Ignacio Gonzalez-Perez, Karsten Bach, Ilhan E. Acar, Nicolás G. Núñez, Daniel Crepaz, Kristina Handler, Vivian P. Vu, Atefeh Lafzi, Kristin Stirm, Deeksha Raju, Julia Gschwend, Konrad Basler, Christoph Schneider, Emma Slack, Tomas Valenta, Burkhard Becher, Philippe Krebs, Andreas E. Moor and Isabelle C. Arnold

Abstract

In the past decade, single-cell transcriptomics has helped uncover new cell types and states and led to the construction of a cellular compendium of health and disease. Still, some difficult-to-sequence cells remain absent from tissue atlases. Eosinophils, elusive granulocytes implicated in a plethora of human pathologies, are among these uncharted cell types. To date, the heterogeneity of eosinophils and the gene programs underpinning their pleiotropic functions remain poorly understood. In the present study, we provide the first comprehensive single-cell transcriptomic profiling of murine eosinophils. We identify an active and a basal population of intestinal eosinophils, differing in their transcriptome, surface proteome and spatial localization. By means of a genome wide CRISPR inhibition screen and functional assays, we dissect a mechanism by which IL-33 and IFN-ɣ induce active eosinophil accumulation in the inflamed colon. Active eosinophils are endowed with bactericidal and T cell regulatory activity, and express the co-stimulatory molecules CD80 and PD-L1. Notably, active eosinophils are enriched in the lamina propria of a small cohort of inflammatory bowel disease patients and tightly associate with CD4+ T cells. Our findings provide novel insights into the biology of this elusive cell type and highlight its crucial contribution to intestinal homeostasis, immune regulation and host defence. Furthermore, we lay a framework for the characterization of eosinophils in human gastrointestinal diseases.

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