Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice – but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse transcription-regulatory programs, including gene regulation by STAT2 and IRF9 independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wildtype mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcription-regulatory state and helps prepare these cells for rapid response to immune stimuli.

Study outline

Data

This section provides access to raw data and analysis results.

Description	Links
Experimental SOPs:	Macrophages and T cells (PDF) Dendritic cells (PDF)
Genome (mm10) browser tracks:	All samples and assays, fully customizable (UCSC Track Hub)
Sequencing data (Uploaded to GEO)	Superseries across all data (GEO SuperSeries GSE204736) RNA-seq data (GEO Series GSE204735) ATAC-seq data (GEO Series GSE204734) Spatial RNA-seq data (GEO Series GSE227168)
Analysis code & data:	Computer code and metadata (Zenodo) Read count matrices of RNA-seq and ATAC-seq samples (ZIP)
Results:	(Table S1) Sequencing statistics of this dataset (XLSX) (Table S2) Differential expression analysis results from homeostatic conditions (XLSX) (Table S3) Differential epigenomic analysis results from homeostatic conditions (XLSX) (Table S4) Differential expression analysis results comparing wildtype samples from homeostatic and ex vivo context deprivation culture conditions (XLSX) (Table S5) Differential epigenomic analysis results comparing wildtype samples from homeostatic and ex vivo context deprivation culture conditions (XLSX) (Table S6) Receptor-ligand pairs inferred from the Tabula Muris and Tabula Sapiens (XLSX) (Table S7) Differential expression analysis results from IFN-β treatment of JAK-STAT mutants (XLSX)

Citation

If you use these data in your research, please cite:

JAK-STAT signaling maintains homeostasis in T cells and macrophages

Nikolaus Fortelny^*, Matthias Farlik^*, Victoria Fife, Anna-Dorothea Gorki, Caroline Lassnig, Barbara Maurer, Katrin Meissl, Marlies Dolezal, Laura Boccuni, Aarathy Ravi Sundar Jose Geetha, Mojoyinola Joanna Ola, Anzhelika Karjalainen, Stephen Shoebridge, Asma Farhat, Ulrike Mann, Rohit Jain, Shweta Tikoo, Nina Zila, Wolfgang Esser-Skala, Thomas Krausgruber, Katarzyna Sitnik, Thomas Penz, Anastasiya Hladik, Tobias Suske, Sophie Zahalka, Martin Senekowitsch, Daniele Barreca, Florian Halbritter, Sabine Macho-Maschler, Wolfgang Weninger, Heidi A. Neubauer, Richard Moriggl, Sylvia Knapp, Veronika Sexl, Birgit Strobl, Thomas Decker^#, Mathias Müller^#, Christoph Bock<sup>#

*</sup> These authors contributed equally to this work
^# These authors contributed equally to this work

Correspondence: matthias.farlik@meduniwien.ac.at (M.F.) and cbock@cemm.at (C.B.)

Journal paper (open access): https://doi.org/10.1038/s41590-024-01804-1
Research Briefing (read link): https://rdcu.be/dGnH0
Vienna JAK-STAT consortium: https://jak-stat.at/