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| Item Type: | Article |
|---|---|
| Title: | Activation of gp130 signaling in T cells drives T(H)17-mediated multi-organ autoimmunity |
| Creators Name: | Baumgartner, F., Bamopoulos, S.A., Faletti, L., Hsiao, H.J., Holz, M., Gonzalez-Menendez, I., Solé-Boldo, L., Horne, A., Gosavi, S., Özerdem, C., Singh, N., Liebig, S., Ramamoorthy, S., Lehmann, M., Demel, U., Kühl, A.A., Wartewig, T., Ruland, J., Wunderlich, F.T., Schick, M., Walther, W., Rose-John, S., Haas, S., Quintanilla-Martinez, L., Feske, S., Ehl, S., Glauben, R. and Keller, U. |
| Abstract: | The IL-6-gp130-STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3(GOF)) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively activated using a transgene, L-gp130, specifically targeted to T cells. Activating gp130 signaling in T cells in vivo resulted in fatal, early onset, multi-organ autoimmunity in mice that resembled human STAT3(GOF) disease. Female mice had more rapid disease progression than male mice. On a cellular level, gp130 signaling induced the activation and effector cell differentiation of T cells, promoted the expansion of T helper type 17 (T(H)17) cells, and impaired the activity of regulatory T cells. Transcriptomic profiling of CD4(+) and CD8(+) T cells from these mice revealed commonly dysregulated genes and a gene signature that, when applied to human transcriptomic data, improved the segregation of patients with transcriptionally diverse STAT3(GOF) mutations from healthy controls. The findings demonstrate that increased gp130-STAT3 signaling leads to T(H)17-driven autoimmunity that phenotypically resembles human STAT3(GOF) disease. |
| Keywords: | Autoimmunity, CD8-Positive T-Lymphocytes, Cytokine Receptor gp130, Inflammation, STAT3 Transcription Factor, Signal Transduction, Animals, Mice |
| Source: | Science Signaling |
| ISSN: | 1945-0877 |
| Publisher: | American Association for the Advancement of Science |
| Volume: | 17 |
| Number: | 824 |
| Page Range: | eadc9662 |
| Date: | 20 February 2024 |
| Official Publication: | https://doi.org/10.1126/scisignal.adc9662 |
| PubMed: | View item in PubMed |
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