Activation of gp130 signaling in T cells drives T(H)17-mediated multi-organ autoimmunity

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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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