IL-9 and Blimp-1 protect the transcriptional identity of group 2 innate lymphocytes in allergic asthma

Allergic asthma is driven by type 2 immune responses, including type 2 innate lymphoid cells (ILC2s). Although ILC2s are activated by the tissue alarmins interleukin (IL)-33 and IL-25, these signals do not intrinsically enforce type 2 identity and the mechanisms that maintain type 2 cytokine expression remain unclear. Here we show that allergen-induced IL-33 and IL-25 rapidly induce IL-9, which in turn upregulates the transcriptional repressor Blimp-1 in ILC2s. Blimp-1 sustains type 2 immunity by directly repressing type 1 inflammatory programs, including expression of interferon-γ and tumor necrosis factor. Deletion of Blimp-1 in ILC2s increased type 1 cytokine production and reduced IL-5 and IL-13 expression, eosinophil recruitment and mucus production in the lung. In contrast, IL-9 expression was enhanced in the absence of Blimp-1, leading to increased mast cell recruitment. Together, these findings identify Blimp-1 as a key regulator of ILC2 transcriptional fidelity that stabilizes type 2 inflammation while constraining divergent inflammatory programs during allergic responses.

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Publication Details

Journal
Nature Immunology
Published
2026-04-24
DOI
https://doi.org/10.1038/s41590-026-02509-3
Primary Topic
IL-33, ST2, and ILC Pathways
Type
article
Field-Weighted Citation Impact
0.00

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article

IL-9 and Blimp-1 protect the transcriptional identity of group 2 innate lymphocytes in allergic asthma

Anthony Marinov, Aaron Yang, Kun He, Harshita Beeravolu et al.
Nature Immunology
IL-33, ST2, and ILC Pathways
article

IL-9 and Blimp-1 protect the transcriptional identity of group 2 innate lymphocytes in allergic asthma

Anthony Marinov, Aaron Yang, Kun He, Harshita Beeravolu, Amanda C. Poholek, Abbe Pannucci, Shilpi Giri, Anuradha Ray, Daniella M. Schwartz, Rachel A. Gottschalk, Jeremy S. Tilstra, Nicolas Bouladoux, Anthony R. Cillo, Arianna Creech, Jinyi Zhang, Yijia Chen, Sagar L. Kale, Yasmine Belkaid, Yibo Zheng
article en

Abstract

Allergic asthma is driven by type 2 immune responses, including type 2 innate lymphoid cells (ILC2s). Although ILC2s are activated by the tissue alarmins interleukin (IL)-33 and IL-25, these signals do not intrinsically enforce type 2 identity and the mechanisms that maintain type 2 cytokine expression remain unclear. Here we show that allergen-induced IL-33 and IL-25 rapidly induce IL-9, which in turn upregulates the transcriptional repressor Blimp-1 in ILC2s. Blimp-1 sustains type 2 immunity by directly repressing type 1 inflammatory programs, including expression of interferon-γ and tumor necrosis factor. Deletion of Blimp-1 in ILC2s increased type 1 cytokine production and reduced IL-5 and IL-13 expression, eosinophil recruitment and mucus production in the lung. In contrast, IL-9 expression was enhanced in the absence of Blimp-1, leading to increased mast cell recruitment. Together, these findings identify Blimp-1 as a key regulator of ILC2 transcriptional fidelity that stabilizes type 2 inflammation while constraining divergent inflammatory programs during allergic responses.

Nature Immunology
National Institutes of Health (US), Institut Pasteur (FR), University of Pittsburgh (US), UPMC Hillman Cancer Center (US), National Institute of Allergy and Infectious Diseases (US), Tsinghua University (CN)
American Lung Association, Tsinghua University, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 20%
IL-33, ST2, and ILC Pathways
DOIOpen Access PDFOpenAlex
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