Blimp-1 integrates alarmin signals in ILC2s and drives proinflammatory functions required for type 2 immunity
Type 2 immunity has evolved to protect against worms but becomes harmful when activated during allergic inflammation. Group 2 innate lymphoid cells (ILC2s) drive type 2 responses by rapidly secreting IL-5 and IL-13. The alarmins, IL-25, IL-33, and TSLP activate ILC2s and are linked to allergic diseases. However, how alarmins connect to the transcriptional networks driving type 2 effector functions remains elusive. Here, we performed RNA sequencing of ILC2s deficient in IL-25, IL-33, or TSLP pathway and identified the transcription factor Blimp-1 as an IL-33-regulated gene in ILC2s. While Blimp-1 was dispensable for ILC2 development, this transcription factor was required for type 2 cytokine production, driving eosinophilia or promoting worm expulsion. Blimp-1 deficiency resulted in reduced IRF4 expression, while Irf4-deficient ILC2s showed diminished Blimp-1 and IL-33 receptor expression, revealing a reciprocal Blimp-1-IRF4 circuit downstream of the IL-33 receptor. These findings expose the Blimp-1-IRF4 axis as an alarmin-regulated transcriptional network controlling ILC2 effector functions required for type 2 immunity.
Authors
- Jazib Uddin (ORCID: https://orcid.org/0000-0001-5303-5213)
- Magdalena Dubik (ORCID: https://orcid.org/0000-0002-4521-0410)
- Andreas Diefenbach (ORCID: https://orcid.org/0000-0002-9176-9530)
- Elizabeth Emanuel (ORCID: https://orcid.org/0000-0003-1532-8618)
- Hans‐Willi Mittrücker (ORCID: https://orcid.org/0000-0001-6166-4191)
- Xuemei Gao (ORCID: https://orcid.org/0000-0002-2949-3609)
- Anita Kowalczyk (ORCID: https://orcid.org/0000-0002-4217-8857)
- Richard Mertens
- Anja E. Hauser (ORCID: https://orcid.org/0000-0002-7725-9526)
- Alexandra Preußer (ORCID: https://orcid.org/0000-0002-8539-9342)
- Pierre S. Leclère (ORCID: https://orcid.org/0000-0002-1794-9461)
- Michael Kofoed-Branzk (ORCID: https://orcid.org/0000-0001-7210-3752)
- Wen Zhang (ORCID: https://orcid.org/0000-0002-9069-3773)
- Patrycja M. Forster
- Laura Velleman (ORCID: https://orcid.org/0009-0002-7347-8067)
- Divija Deshpande
- Christoph S.N. Klose
- Hiroshi Yano
- David Artis
Institutions
- Universität Hamburg (DE)
- Cornell University (US)
- Humboldt-Universität zu Berlin (DE)
- German Rheumatism Research Centre (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2026-03-31
- DOI
- https://doi.org/10.1084/jem.20250781
- Citations
- 1
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 12.26
Funders
- Crohn's and Colitis Foundation
- Deutsche Forschungsgemeinschaft
- Charité – Universitätsmedizin Berlin
- Lundbeckfonden
- Einstein Stiftung Berlin
- National Institutes of Health
- Weill Cornell Medicine
- H2020 European Research Council