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

• Published in: Science signaling 2024-02, Vol.17 (824), p.eadc9662
• Main Authors: Baumgartner, Francis, Bamopoulos, Stefanos A, Faletti, Laura, Hsiao, Hsiang-Jung, Holz, Maximilian, Gonzalez-Menendez, Irene, Boldo, Llorenç, Horne, Arik, Gosavi, Sanket, Özerdem, Ceren, Singh, Nikita, Liebig, Sven, Ramamoorthy, Senthilkumar, Lehmann, Malte, Demel, Uta, Kühl, Anja A, Wartewig, Tim, Ruland, Jürgen, Wunderlich, Frank T, Schick, Markus, Walther, Wolfgang, Rose-John, Stefan, Haas, Simon, Quintanilla-Martinez, Leticia, Feske, Stefan, Ehl, Stephan, Glauben, Rainer, Keller, Ulrich
• Format: Article
• Language: English
• Subjects: Animals; Autoimmunity - genetics; CD8-Positive T-Lymphocytes - metabolism; Cytokine Receptor gp130 - genetics; Cytokine Receptor gp130 - metabolism; Female; Humans; Inflammation; Male; Mice; Signal Transduction; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism
• ISSN: 1945-0877; 1937-9145
• DOI: 10.1126/scisignal.adc9662

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 ) 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, , 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 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 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 mutations from healthy controls. The findings demonstrate that increased gp130-STAT3 signaling leads to T 17-driven autoimmunity that phenotypically resembles human STAT3 disease.