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| Status |
Public on Oct 01, 2023 |
| Title |
Activation of gp130 signaling in T-cells drives TH17-mediated multi-organ autoimmunity |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Purpose: Recently discovered activating Interleukin-6 receptor subunit beta (IL6ST, encoding glycoprotein 130 (gp130)) mutations, as well as germline Signal transducer and activator of transcription 3 (STAT3) gain-of-function mutations are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis, resulting in an unmet medical need.
Methods: To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, in this study we constitutively activated the gp130/JAK/STAT3 axis by means of a transgene, L-gp130, specifically targeted to T-cells.
Results: Activating gp130 signaling in vivo resulted in fatal early-onset multi-organ autoimmunity, resembling numerous clinical features of human STAT3 gain-of-function disease. We observed strong T-cell activation and effector differentiation, accompanied by TH17 expansion and interferon-gamma production. Transcriptome profiling of murine CD4+ and CD8+ T-cells revealed commonly dysregulated genes and a STAT3 gain-of-function signature that was used to discriminate between STAT3 gain-of-function and healthy control patients.
Conclusions: Hyperactive gp130/STAT3 signaling leads to strong TH17-mediated autoimmunity phenotypically resembling human STAT3 gain-of-function disease and identify TH17-cells as a key cellular subset for initiation and maintenance of autoimmunity
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| Overall design |
Purified splenic CD4+ and CD8+ T-cell mRNA profiles of 5 weeks old CD4Cre+/− (control) and L-gp130fl/+;CD4Cre+/− mice
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| Contributor(s) |
Baumgartner F, Bamopoulos SA, Keller U |
| Citation missing |
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| |
| Submission date |
Mar 17, 2022 |
| Last update date |
Oct 02, 2023 |
| Contact name |
Francis G Baumgartner |
| Organization name |
Charité University Medicine Berlin
|
| Street address |
Hindenburgdamm 30
|
| City |
Berlin |
| ZIP/Postal code |
12203 |
| Country |
Germany |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (21)
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| Relations |
| BioProject |
PRJNA817172 |
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