IL-7-glucose-Aiolos axis orchestrates pathogenic CD8+ T cell function in spondyloarthritis

• 成果类型: Article
• 署名作者: Akiyama, Mitsuhiro; Alshehri, Waleed; Koroyasu, Mirei; Kaburaki, Tomohiro; Yoshimoto, Keiko; Saito, Koichi; Shimanuki, Kanako; Kaneko, Yuko
• 署名单位: Keio University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2536238123
• 发表日期: 2026-07-21
• 页码: e2536238123
• 关键词: Interleukin-7; glucose transporter; Janus kinase; aiolos; CD8(+) T cells; SOCIETY CLASSIFICATION CRITERIA; PSORIATIC-ARTHRITIS; modulator; therapy; ikaros; cxcr3

摘要

CD8(+) T cells are essential mediators of host defense, whereas their aberrant activation contributes to inflammatory diseases such as spondyloarthritis. The molecular mechanisms governing human CD8(+) T cell effector programming remain incompletely understood. Here, we identify a metabolically distinct subset of human CD8(+) T cells defined by high expression of CXCR3, IL-7R, and GLUT1 and low expression of the transcription factor Aiolos. IL-7-JAK-STAT signaling was associated with increased GLUT1 expression and glucose uptake, accompanied by reduced Aiolos expression in CD8(+) T cells. Consistent with this, Aiolos functioned as a regulatory constraint on effector cytokine production under glucose-limited conditions, and its reduction was associated with enhanced cytokine production in metabolically active CD8(+) T cells. Circulating CD8(+) T cells from patients with spondyloarthritis exhibited elevated GLUT1 expression compared with rheumatoid arthritis and healthy controls, which correlated with disease activity. In addition, CXCR3(+) IL-7R(+) pSTAT5(+) GLUT1(+) Aiolos(low) CD8(+) T cells were enriched in inflamed joints, where CXCL10 may contribute to their recruitment. Increased FDG uptake in inflamed sacroiliac joints further supports enhanced metabolic activity at sites of inflammation. JAK inhibitor therapy was associated with reduced GLUT1 expression and increased Aiolos expression in CD8(+) T cells, accompanied by decreased effector cytokine production and clinical improvement in patients with spondyloarthritis. Together, these findings support a model in which cytokine signaling, metabolic state, and transcriptional regulation are functionally linked in human CD8(+) T cells, and suggest that Aiolos may act as a regulatory node integrating these inputs in inflammatory diseases.