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

Objective 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. Methods 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. Results 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. Conclusion 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. image