Persistent IL-18 fuels expansion of CD38⁺HLA-DR⁺CD8⁺ T cells in Still's disease and macrophage activation syndrome.

Abstract

Still's disease (SD) is an autoinflammatory disorder characterized by remarkably high IL-18 levels. Increasing evidence suggests that adaptive immunity also contributes to its pathogenesis, particularly in refractory courses. Macrophage activation syndrome (MAS), one of SD's most severe complications, is associated with further IL-18 elevation and expansion of CD38⁺HLA-DR⁺CD8⁺ T cells. However, whether and when this population emerges during SD remains unknown. We therefore examined CD38⁺HLA-DR⁺CD8⁺ T cells across disease stages. CD38⁺HLA-DR⁺CD8⁺ T cells were analyzed longitudinally: at SD-onset (therapy-naïve; n=19), during clinically inactive disease (n=15), and prior to or at MAS occurrence (n=12). Spectral flow cytometry and bulk RNA-sequencing were performed. Correlations with clinical and laboratory parameters were assessed. In vitro cytokine stimulations of healthy donor (HD)-derived PBMCs and CD8⁺ lymphocytes were performed to explore mechanisms driving differentiation of these cells. CD38⁺HLA-DR⁺CD8⁺ T cells were expanded from SD-onset and peaked in MAS (median: 4.61% and 31.7%, respectively, versus 0.87% in HD). Transcriptomic profiling of these cells revealed enrichment of activation, cytotoxicity, and proliferation programs, which were confirmed at the protein level. Frequencies correlated with markers of systemic inflammation, T-cell activation, and serum IL-18 levels. Sustained IL-18 stimulation in vitro induced robust and persistent expansion of CD38⁺HLA-DR⁺CD8⁺ cells, recapitulating key ex vivo phenotypic features. CD38⁺HLA-DR⁺CD8⁺ cells, previously primarily associated with MAS, are detectable early in SD. Persistent IL-18 exposure promotes their expansion. These findings identify CD38⁺HLA-DR⁺CD8⁺ T cells as a potential mechanistic link between SD and MAS and highlight this subset as a candidate therapeutic target.