Rapamycin improves Graves’ orbitopathy by suppressing CD4(+) cytotoxic T lymphocytes

CD4(+) cytotoxic T lymphocytes (CTLs) were recently implicated in immune-mediated inflammation and fibrosis progression of Graves’ orbitopathy (GO). However, little is known about therapeutic targeting of CD4(+) CTLs. Herein, we studied the effect of rapamycin, an approved mTOR complex 1 (mTORC1) inhibitor, in a GO mouse model, in vitro, and in patients with refractory GO. In the adenovirus-induced model, rapamycin significantly decreased the incidence of GO. This was accompanied by the reduction of both CD4(+) CTLs and the reduction of orbital inflammation, adipogenesis, and fibrosis. CD4(+) CTLs from patients with active GO showed upregulation of the mTOR pathway, while rapamycin decreased their proportions and cytotoxic function. Low-dose rapamycin treatment substantially improved diplopia and the clinical activity score in steroid-refractory patients with GO. Single-cell RNA-Seq revealed that eye motility improvement was closely related to suppression of inflammation and chemotaxis in CD4(+) CTLs. In conclusion, rapamycin is a promising treatment for CD4(+) CTL-mediated inflammation and fibrosis in GO.