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

Item Type:	Article
Title:	Activation of gp130 signaling in T cells drives T(H)17-mediated multi-organ autoimmunity
Creators Name:	Baumgartner, F. and Bamopoulos, S.A. and Faletti, L. and Hsiao, H.J. and Holz, M. and Gonzalez-Menendez, I. and Solé-Boldo, L. and Horne, A. and Gosavi, S. and Özerdem, C. and Singh, N. and Liebig, S. and Ramamoorthy, S. and Lehmann, M. and Demel, U. and Kühl, A.A. and Wartewig, T. and Ruland, J. and Wunderlich, F.T. and Schick, M. and Walther, W. and Rose-John, S. and Haas, S. and Quintanilla-Martinez, L. and Feske, S. and Ehl, S. and 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

Repository Staff Only: item control page