Activation of gp130 signaling in T cells drives TH17-mediated multi-organ autoimmunity.

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_H17) 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_H17-driven autoimmunity that phenotypically resembles human STAT3^GOF disease. Editor's summary: Gain-of-function mutations in the transcription activator STAT3 cause an autoimmune disease called STAT3^GOF syndrome. A challenging feature of this syndrome is the phenotypic heterogeneity of the individual STAT3 mutations. By manipulating an upstream activator instead of STAT3 itself, Baumgartner et al. developed a mouse model that recapitulated more aspects of the disease. Mice with constitutive activation of the cytokine receptor subunit gp130 in T cells developed fatal, multi-organ inflammation with changes in T cell profiles and gene expression that were similar to those in patients with STAT3^GOF autoimmunity, suggesting that this model may be useful for investigating the disease and exploring therapeutic options. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR]